About HRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
HRAS c.374T>C, p.(Val125Ala)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen HRAS VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PP2Supporting
PP2 · supporting
The RASopathy VCEP specifies PP2 as applicable to all RASopathy genes curated in the specification. HRAS is a RASopathy gene, and this is a missense variant (p.Val125Ala). Per VCEP: 'PP2 is applicable to all RASopathy genes described and curated herein.'
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PP2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
2 / 1,613,828 alleles
gnomAD v4.1: 2 / 1,613,828 alleles. Recorded AF 1.23929e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HRAS, a GTPase, is altered in a diverse range of cancers including head and neck squamous cell carcinoma, thyroid, and bladder cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen HRAS VCEP v1.0, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PP2 was applied at supporting strength per RASopathy VCEP specification, as PP2 is applicable to all RASopathy genes curated by this expert panel.
The variant p.Val125Ala is present in gnomAD v4.1 at extremely low frequency (2/1,613,828 alleles; AF = 1.24e-6), precluding PM2 (requires complete absence per VCEP) but remaining far below BA1 (>=0.05%) and BS1 (>=0.025%) thresholds.
No functional studies have characterized p.Val125Ala in any VCEP-approved assay; PS3 and BS3 cannot be applied.
The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories, ClinVar ID 981547) with criteria provided by a single submitter. No expert panel review has been performed.
No criteria match.
Met · 1
PP2 SupportingThe RASopathy VCEP specifies PP2 as applicable to all RASopathy genes curated in the specification. HRAS is a RASopathy gene, and this is a missense variant (p.Val125Ala). Per VCEP: 'PP2 is applicable to all RASopathy genes described and curated herein.' Details ▾Hide ▴
Evidence considered
- RASopathy VCEP: PP2 applicable to all curated RASopathy genes including HRAS
- Variant is missense in a gene where missense variants are a common mechanism of disease
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (p.Val125Ala) has been identified in HRAS. No analogous pathogenic missense at this position has been reported in Group 1 genes (HRAS, NRAS, KRAS). Details ▾Hide ▴
PS2 No de novo occurrence with confirmed paternity has been reported in the literature for this variant. ClinVar submissions do not include de novo annotation. Details ▾Hide ▴
Evidence considered
- ClinVar submissions do not report de novo status for this variant
Still missing
- No segregation or parent-of-origin data available
Sources
PS3 The RASopathy VCEP-approved functional studies (RAS Activation Assay, MEK Activation Assay, ERK Activation Assay) have been validated for HRAS, but the specific variant p.Val125Ala (V125A) is not among the validation controls tested in any approved study. No functional data have been published for this exact variant in any VCEP-approved assay. Per VCEP READ ME, assays not listed lack sufficient historical evidence to evaluate functional impact of a given variant and may only be sufficient for PS3_Supporting; however, without any assay data for V125A, even supporting-level evidence cannot be applied. Details ▾Hide ▴
Evidence considered
- VCEP-approved HRAS functional assays exist (RAS
- MEK
- ERK activation) but V125A is not among tested variants
- OncoKB classifies the variant as Unknown Oncogenic Effect with no variant-specific functional evidence
Still missing
- No functional characterization of p.Val125Ala in any VCEP-approved assay
Sources
PS4 No independent occurrences meeting the VCEP threshold have been identified. The variant has been reported in ClinVar as Uncertain significance by 2 clinical laboratories but no specific proband counts or case-level data are available. No published case reports or case series describe individuals with this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical laboratory submissions
- both classified as Uncertain significance
- No published case observations in reviewed literature
Still missing
- No proband counting data available
- No case-control studies
Sources
PM1 Position 125 is not located within a VCEP-approved PM1 functional domain. The approved domains for HRAS are the P-loop (residues 10-17) and Switch I (residues 25-40). Position 125 lies in the C-terminal region of HRAS outside these domains. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domains: P-loop (HRAS 10-17)
- Switch I (HRAS 25-40)
- V125A is outside these regions
- Cancerhotspots.org: residue not significant
- exact variant not listed
Sources
vcep_alignment_with_pm1_domains_pptxcspec ↗
PM2 The RASopathy VCEP requires complete absence from all population databases for PM2 application. The variant is present in gnomAD v4.1 with 2 alleles (AF = 1.24e-6, 2/1,613,828 alleles in the European non-Finnish population), thus it is not completely absent. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2/1
- 613
- 828 alleles (AF = 1.24e-6)
- highest in NFE (2/1
- 179
- 970)
- VCEP PM2 rule: must be completely absent from all population databases
Sources
PM5 No pathogenic missense variant at the same amino acid residue (position 125) has been identified in HRAS. PM5 candidate search returned zero same-residue comparator variants. No analogous pathogenic missense at this position has been identified in Group 1 genes (HRAS, NRAS, KRAS). Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- No established pathogenic missense at HRAS position 125
Sources
pm5_candidatescspec ↗
PM6 No assumed or confirmed de novo occurrence has been reported in the literature for this variant. ClinVar submissions do not include de novo annotation. Details ▾Hide ▴
Evidence considered
- ClinVar: no de novo annotation in submissions
- No published de novo reports identified
Still missing
- No de novo reports available
Sources
PP1 No co-segregation data are available. The VCEP requires at least three informative meioses for PP1_Supporting; no family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family segregation data reported
Still missing
- No segregation or family studies available
Sources
PP3 The VCEP requires multiple lines of computational evidence supporting a deleterious effect. REVEL score (0.879) supports a deleterious effect, but BayesDel (0.122) is equivocal and does not clearly support pathogenicity. SpliceAI (max delta 0.00) predicts no splice impact. HCI prior is unavailable for HRAS. Only one in silico predictor (REVEL) clearly supports a deleterious effect, which does not constitute multiple lines of evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.879 (deleterious)
- BayesDel: 0.122 (equivocal
- does not independently support deleterious effect)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: not available for HRAS
Still missing
- Contradictory in silico predictions
- REVEL alone is insufficient for multiple lines
Sources
BA1 The VCEP BA1 threshold is allele frequency >= 0.05%. The variant frequency in gnomAD v4.1 is 1.24e-6 (0.00012%), far below the stand-alone benign threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF: 1.24e-6 (0.00012%)
- VCEP BA1 threshold: >= 0.05% (≥ 0.0005)
Sources
BS1 The VCEP BS1 threshold is allele frequency >= 0.025%. The variant frequency in gnomAD v4.1 is 1.24e-6 (0.00012%), an order of magnitude below the strong benign threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF: 1.24e-6 (0.00012%)
- VCEP BS1 threshold: >= 0.025% (≥ 0.00025)
Sources
BS2 The VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. Clinical laboratories are encouraged to accumulate more than 3 instances of well-phenotyped family members before applying this criterion. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
- VCEP BS2: requires well-phenotyped family members
- not population data
- No family member phenotype data available
Still missing
- No well-phenotyped healthy adult carriers identified
Sources
BS3 No VCEP-approved functional studies have been performed for this variant. The RASopathy VCEP-approved functional assays for HRAS have not tested p.Val125Ala. No evidence exists that this variant has no damaging effect on protein function. Details ▾Hide ▴
Evidence considered
- VCEP-approved HRAS functional assays do not include V125A
- No functional data demonstrating normal protein function for this variant
Still missing
- No functional characterization of p.Val125Ala
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
BS4 The VCEP requires one informative meiosis demonstrating lack of segregation. No family studies or segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data or family studies reported
Still missing
- No informative meioses data available
Sources
BP2 No evidence that this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase information or co-occurrence data available
Still missing
- No phase data with other HRAS variants
Sources
BP4 The VCEP requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL (0.879) predicts a deleterious effect, which contradicts the requirement. While SpliceAI (max delta 0.00) predicts no splice impact and BayesDel (0.122) is equivocal, the REVEL score alone precludes multiple lines of evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.879 (deleterious
- contradicts no-impact hypothesis)
- SpliceAI: max delta 0.00 (no splice impact)
- BayesDel: 0.122 (equivocal)
Sources
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. No proband-level clinical data are available. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular diagnosis identified
Still missing
- No proband clinical or molecular data available
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP specifies PVS1 as not applicable for RASopathy genes; LOF/haploinsufficiency has not been clearly identified as a disease mechanism for the RASopathy spectrum phenotype. Additionally, this is a missense variant (p.Val125Ala), which does not fall into null-variant categories. Details ▾Hide ▴
Evidence considered
- RASopathy VCEP v1.0 explicitly designates PVS1 as Not Applicable for this VCEP
Sources
PP4 VCEPThe RASopathy VCEP specifies PP4 as Not Applicable for this VCEP. Per the specification: 'This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.' Details ▾Hide ▴
Evidence considered
- RASopathy VCEP: PP4 explicitly designated Not Applicable for this VCEP
Sources
PP5 VCEPThe RASopathy VCEP specifies PP5 as Not Applicable for this VCEP. Per the specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Evidence considered
- RASopathy VCEP: PP5 explicitly designated Not Applicable for this VCEP
Sources
BP1 N/AThe VCEP specifies BP1 for truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene/exon deletion) in genes without established LOF correlation to disease. This is a missense variant (p.Val125Ala) and does not meet the variant type requirements for BP1. Details ▾Hide ▴
Evidence considered
- VCEP BP1: applicable only to truncating variants
- V125A is a missense substitution
Sources
BP6 VCEPThe RASopathy VCEP specifies BP6 as Not Applicable for this VCEP. Per the specification: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
Evidence considered
- RASopathy VCEP: BP6 explicitly designated Not Applicable for this VCEP
Sources
BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants for which splicing prediction algorithms predict no impact. This is a missense variant (c.374T>C, p.Val125Ala) and does not meet the variant type requirements for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7: applicable only to synonymous or intronic/non-coding variants
- c.374T>C is a missense substitution
Sources
PS5 N/APS5 is not included in the ClinGen RASopathy VCEP specification. The criterion is not applicable under this framework. Details ▾Hide ▴
Identifiers
- Gene
- HRAS
- Transcript
- NM_001130442.2
- Coding (HGVS c.)
- NM_001130442.2:c.374T>C
- Protein (HGVS p.)
- NP_001123914.1:p.(Val125Ala)
- GRCh38
- chr11:533529 A>G
- GRCh37
- chr11:533529 A>G
- ClinVar
- 981547
Gene diagram
Every interpreted variant in HRAS, mapped onto the exon structure of NM_001130442.2. Select a row to find it on the plot.
HRASNM_001130442.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in HRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
2 / 1,613,828 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,828 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,179,970 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23929e-06; MAF= 0.00012%, 2/1613828 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69496e-06; MAF= 0.00017%, 2/1179970 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.879
- BayesDel
- 0.122
How the predictions were used
PP3 The VCEP requires multiple lines of computational evidence supporting a deleterious effect. REVEL score (0.879) supports a deleterious effect, but BayesDel (0.122) is equivocal and does not clearly support pathogenicity. SpliceAI (max delta 0.00) predicts no splice impact. HCI prior is unavailable for HRAS. Only one in silico predictor (REVEL) clearly supports a deleterious effect, which does not constitute multiple lines of evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.879 (deleterious)
- BayesDel: 0.122 (equivocal
- does not independently support deleterious effect)
- SpliceAI: max delta 0.00 (no splice impact)
- HCI prior: not available for HRAS
Still missing
- Contradictory in silico predictions
- REVEL alone is insufficient for multiple lines
Sources
BP4 The VCEP requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL (0.879) predicts a deleterious effect, which contradicts the requirement. While SpliceAI (max delta 0.00) predicts no splice impact and BayesDel (0.122) is equivocal, the REVEL score alone precludes multiple lines of evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
- REVEL: 0.879 (deleterious
- contradicts no-impact hypothesis)
- SpliceAI: max delta 0.00 (no splice impact)
- BayesDel: 0.122 (equivocal)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants for which splicing prediction algorithms predict no impact. This is a missense variant (c.374T>C, p.Val125Ala) and does not meet the variant type requirements for BP7. Details ▾Hide ▴
Evidence considered
- VCEP BP7: applicable only to synonymous or intronic/non-coding variants
- c.374T>C is a missense substitution
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.121936.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301303 ↗Noonan Syndrome.Adam MP et al. · 1993GeneReviews entry for Noonan Syndrome. No abstract or full text available for review; indexed as a clinical overview. No specific variant data expected.Does not name this variant
-
PMID 20301680 ↗HRAS-Related Costello Syndrome.Adam MP et al. · 1993GeneReviews entry for HRAS-Related Costello Syndrome. No abstract or full text available for review; indexed as a clinical overview. No specific variant data expected.Does not name this variant
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PMID 20876176 ↗Noonan syndrome: clinical features, diagnosis, and management guidelines.Romano AA et al. · 2010Clinical review and management guidelines for Noonan syndrome. Discusses HRAS mutations as causative for Costello syndrome at the gene level but does not mention NM_001130442.2:c.374T>C (p.Val125Ala).Does not name this variant
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PMID 25173338 ↗2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).Authors/Task Force members et al. · 20142014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Background review paper; does not contain specific variant data for HRAS or any RASopathy gene.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,613,828 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637576
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/981547/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-533529-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-533529-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-533529-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001130442.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/HRAS/V125A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=HRAS+c.374T%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23929e-06; MAF= 0.00012%, 2/1613828 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69496e-06; MAF= 0.00017%, 2/1179970 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 981547)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.879. BayesDel score = 0.121936.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HRAS, a GTPase, is altered in a diverse range of cancers including head and neck squamous cell carcinoma, thyroid, and bladder cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.