About HRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
HRAS c.403C>G, p.(Arg135Gly)
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
PP2 is explicitly applicable to all RASopathy genes per the VCEP specification. HRAS is a RASopathy gene where missense variants are a common mechanism of disease, and this variant is a missense change (p.Arg135Gly).
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 / 1,613,606 alleles
gnomAD v4.1: 2 / 1,613,606 alleles. Recorded AF 1.23946e-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
1 reported laboratory submissions
1 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.
29 criteria with recorded statuses: 1 met · 18 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005343.4:c.403C>G (p.Arg135Gly) is a missense variant in HRAS, a RASopathy gene. Only one criterion is met: PP2 at supporting strength, which applies to all RASopathy missense variants per the ClinGen RASopathy VCEP specification.
This variant is present in gnomAD v4.1 at extremely low frequency (2/1,613,606 alleles, AF ~0.00012%), with single alleles observed in South Asian and European (non-Finnish) populations. It is absent from gnomAD v2.1 and gnomAD-Canada.
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (GeneDx, VCID 3371962) with criteria provided. No expert panel review or pathogenic classification exists.
Computational predictions are mixed: REVEL score 0.423 is intermediate, BayesDel score -0.136 leans benign, and SpliceAI predicts no splice impact (max delta 0.00). These do not converge on a consistent pathogenic or benign prediction.
Position 135 is not within a VCEP-approved PM1 functional domain (P-loop residues 10-17; Switch I residues 25-40) and is not identified as a statistically significant hotspot by cancerhotspots.org.
No functional studies have tested p.Arg135Gly in VCEP-approved assays (RAS Activation, MEK Activation, ERK Activation). The VCEP validation controls for HRAS are limited to G-domain residues (G12, G13, G60, K117, A146) and do not extend to position 135.
No de novo occurrences, segregation data, or case-control studies exist for this variant. No literature publications were identified that mention this specific variant.
With only PP2 (supporting) met and no other criteria fulfilled, this variant is classified as a Variant of Uncertain Significance (VUS) per the ACMG/AMP framework as modified by the ClinGen RASopathy VCEP.
No criteria match.
Met · 1
PP2 SupportingPP2 is explicitly applicable to all RASopathy genes per the VCEP specification. HRAS is a RASopathy gene where missense variants are a common mechanism of disease, and this variant is a missense change (p.Arg135Gly). Details ▾Hide ▴
Evidence considered
- VCEP states: 'PP2 is applicable to all RASopathy genes described and curated herein.' HRAS is a RASopathy gene
- variant is missense.
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No evidence that p.Arg135Gly has been previously established as a pathogenic variant per VCEP criteria. This exact amino acid change has not been reported as pathogenic in germline RASopathy. Details ▾Hide ▴
Evidence considered
- ClinVar lists this variant as Uncertain significance (1 submitter
- GeneDx)
- no prior pathogenic classification for p.Arg135Gly.
Still missing
- No prior pathogenic classification exists for p.Arg135Gly in any database.
Sources
PS2 No de novo occurrence data is available for this variant. The VCEP requires confirmed de novo (paternity confirmed) in a patient with RASopathy and no family history for PS2 at strong strength. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature.
Still missing
- No de novo data
- no parental testing reported.
PS3 VCEP-approved functional assays (RAS Activation, MEK Activation, ERK Activation) exist for HRAS, but the specific variant p.Arg135Gly has not been tested in any approved study. The VCEP validation controls cover G-domain residues (G12, G13, G60, K117, A146) and do not extend to position 135 in the C-terminal region. Details ▾Hide ▴
Evidence considered
- VCEP functional studies spreadsheet lists approved assays for HRAS but validation controls are limited to G-domain residues
- position 135 is not among tested variants.
Still missing
- No functional data exists for p.Arg135Gly
- variant is in C-terminal region outside validated G-domain controls.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No confirmed independent occurrences of this variant in individuals with RASopathy phenotypes. A single ClinVar submission from GeneDx classifies it as Uncertain significance with condition 'Not Provided.' VCEP requires ≥1 (supporting), ≥3 (moderate), or ≥5 (strong) independent occurrences in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar VCID 3371962: 1 submission (GeneDx)
- Uncertain significance
- condition 'Not Provided'
- no confirmed RASopathy phenotype.
Still missing
- Zero confirmed occurrences in RASopathy-affected individuals.
Sources
PM1 Position 135 is not within a VCEP-approved functional domain. The approved PM1 domains for HRAS are P-loop (residues 10-17) and Switch I (residues 25-40). Position 135 lies in the C-terminal portion of the G-domain, outside these domains. cancerhotspots.org does not identify this residue as a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domains: P-loop (10-17)
- Switch I (25-40)
- position 135 not included.
- Cancerhotspots.org: residue not significant
- exact variant not listed.
Sources
vcep_alignment_with_pm1_domains_pptx
PM2 VCEP PM2 requires complete absence from all population databases. This variant is present in gnomAD v4.1 at 2/1,613,606 alleles (AF ~0.00012%), with 1 allele in South Asian and 1 in European (non-Finnish) populations. Presence in a population database disqualifies PM2 under the VCEP rule. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 2/1
- 613
- 606 alleles (AF=1.24e-6
- 0.00012%)
- 1 SAS
- 1 NFE. Absent from gnomAD v2.1 and gnomAD-Canada.
Sources
PM5 No candidate pathogenic missense variants at Arg135 were identified. PM5 requires a different pathogenic missense change at the same residue, established as pathogenic per VCEP criteria. No such comparator exists for Arg135 in the available data. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue candidates
- no pathogenic missense variants at Arg135 identified.
Still missing
- No pathogenic comparators at Arg135
- residue not previously characterized as a disease-associated position in RASopathies.
Sources
pm5_candidates
PM6 No de novo data (with or without parentage confirmation) is available for this variant. VCEP PM6 requires confirmed de novo without confirmation of paternity and maternity at moderate strength, or ≥2 independent occurrences at strong strength. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in any data source.
Still missing
- No de novo data available.
PP1 No co-segregation data is available. VCEP PP1 requires at least three informative meioses at supporting strength. No family studies or segregation data exist for this variant. Details ▾Hide ▴
Evidence considered
- No segregation or family data reported.
Still missing
- No co-segregation or informative meiosis data.
PP3 Computational evidence is mixed and does not consistently support a deleterious effect. REVEL score 0.423 is intermediate (below the typical pathogenic threshold of 0.5), BayesDel score -0.136 leans benign, and SpliceAI max delta 0.00 predicts no splice impact. Multiple lines do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.423 (intermediate/borderline).
- BayesDel: -0.136 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
Still missing
- In silico predictions are ambiguous
- none strongly support pathogenicity.
Sources
BA1 VCEP BA1 threshold is allele frequency ≥0.05%. The highest observed population frequency is 0.0011% (South Asian, gnomAD v4.1), far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 0.0011% (South Asian)
- total AF = 0.00012%. VCEP BA1 threshold = 0.05%.
Sources
BS1 VCEP BS1 threshold is allele frequency ≥0.025%. The highest observed population frequency is 0.0011% (South Asian, gnomAD v4.1), far below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: max subpopulation AF = 0.0011% (South Asian)
- total AF = 0.00012%. VCEP BS1 threshold = 0.025%.
Sources
BS2 VCEP BS2 specifically states that general population data should not be used; it requires well-phenotyped family members. No data on healthy adult individuals carrying this variant with confirmed RASopathy-negative clinical workup is available. Details ▾Hide ▴
Evidence considered
- No well-phenotyped healthy individuals carrying this variant reported. VCEP cautions against using population data for BS2.
Still missing
- No phenotype data for the 2 gnomAD carriers
- no clinical workup reported.
BS3 No functional studies demonstrating no damaging effect exist for p.Arg135Gly. VCEP-approved functional assays (RAS Activation, MEK Activation, ERK Activation) have not tested this variant. Details ▾Hide ▴
Evidence considered
- No functional data exists for this variant in VCEP-approved or other assays.
Still missing
- No functional data (benign or pathogenic) exists for p.Arg135Gly.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4 No segregation data is available for this variant. VCEP BS4 requires at least one informative meiosis showing lack of segregation. No family studies exist. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation or family studies reported.
BP2 No data on trans or cis phase with a pathogenic variant is available. No co-occurrence data exists for this variant. Details ▾Hide ▴
Evidence considered
- No phase data or co-occurrence with pathogenic variants reported.
Still missing
- No trans/cis phase data with pathogenic variants.
BP4 Computational evidence is mixed and does not consistently suggest no impact on the gene product. While SpliceAI (max delta 0.00) predicts no splice effect and BayesDel (-0.136) leans benign, REVEL (0.423) is intermediate and does not clearly support a benign interpretation. The multiple lines do not converge on a benign prediction sufficient to meet VCEP BP4 requirements. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.00 (no splice impact).
- BayesDel: -0.136 (benign-leaning).
- REVEL: 0.423 (intermediate
- not clearly benign).
Still missing
- In silico predictions are ambiguous
- REVEL score does not clearly support benign effect.
Sources
BP5 No evidence that this variant has been observed in a case with an alternate molecular basis for disease. No co-occurring pathogenic variant in another RASopathy gene has been reported. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular diagnosis identified.
Still missing
- No data on alternate molecular diagnoses in carriers.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP explicitly designates PVS1 as Not Applicable because loss-of-function and/or haploinsufficiency has not been clearly identified as a disease mechanism for RASopathy genes. Additionally, NM_005343.4:c.403C>G (p.Arg135Gly) is a missense variant and does not fall into any null-variant category. Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks PVS1 as Not Applicable for RASopathy genes
- variant is missense
- not a null variant.
Sources
PM3 VCEPVCEP explicitly designates PM3 as Not Applicable because this criterion applies to recessive disorders and is not applicable to the autosomal dominant RASopathies. Details ▾Hide ▴
Sources
PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions and stop-loss variants. This is a missense substitution, not a protein-length-altering variant. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPThe ClinGen RASopathy VCEP explicitly designates PP4 as Not Applicable. Patient phenotype specificity criteria are not used for RASopathies; PS4 proband counting is used instead. Details ▾Hide ▴
Evidence considered
- VCEP: 'This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.'
Sources
PP5 VCEPThe ClinGen RASopathy VCEP explicitly designates PP5 as not for use, per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
- VCEP: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
BP1 N/AVCEP BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice, initiation codon, multi-exon deletion) in genes without established LOF correlation to disease. This variant is a missense substitution, not a truncating variant, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule targets truncating variants only
- c.403C>G is a missense variant.
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPThe ClinGen RASopathy VCEP explicitly designates BP6 as not for use, per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
- VCEP: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant (c.403C>G) is a missense substitution (p.Arg135Gly), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule targets synonymous variants
- c.403C>G is a missense variant.
Sources
PS5 N/APS5 is not a recognized ACMG/AMP criterion. It does not exist in the standard ACMG/AMP 2015 framework or in the ClinGen RASopathy VCEP specifications. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- HRAS
- Transcript
- NM_005343.4
- Coding (HGVS c.)
- NM_005343.4:c.403C>G
- Protein (HGVS p.)
- NP_005334.1:p.(Arg135Gly)
- GRCh38
- chr11:533500 G>C
- GRCh37
- chr11:533500 G>C
- ClinVar
- 3371962
Gene diagram
Every interpreted variant in HRAS, mapped onto the exon structure of NM_005343.4. Select a row to find it on the plot.
HRASNM_005343.4
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 / 1,613,606 alleles
AF 1.24e-06 · 0 homozygotes
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 / 1,613,606 alleles · 0 hom
| South Asian1 / 91,088 | 1.1e-05 |
| European (non-Finnish)1 / 1,179,976 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23946e-06; MAF= 0.00012%, 2/1613606 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09784e-05; MAF= 0.00110%, 1/91088 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.423
- BayesDel
- -0.136
How the predictions were used
PP3 Computational evidence is mixed and does not consistently support a deleterious effect. REVEL score 0.423 is intermediate (below the typical pathogenic threshold of 0.5), BayesDel score -0.136 leans benign, and SpliceAI max delta 0.00 predicts no splice impact. Multiple lines do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.423 (intermediate/borderline).
- BayesDel: -0.136 (benign-leaning).
- SpliceAI: max delta 0.00 (no splice impact).
Still missing
- In silico predictions are ambiguous
- none strongly support pathogenicity.
Sources
BP4 Computational evidence is mixed and does not consistently suggest no impact on the gene product. While SpliceAI (max delta 0.00) predicts no splice effect and BayesDel (-0.136) leans benign, REVEL (0.423) is intermediate and does not clearly support a benign interpretation. The multiple lines do not converge on a benign prediction sufficient to meet VCEP BP4 requirements. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.00 (no splice impact).
- BayesDel: -0.136 (benign-leaning).
- REVEL: 0.423 (intermediate
- not clearly benign).
Still missing
- In silico predictions are ambiguous
- REVEL score does not clearly support benign effect.
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This variant (c.403C>G) is a missense substitution (p.Arg135Gly), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- VCEP BP7 rule targets synonymous variants
- c.403C>G is a missense variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.423. BayesDel score = -0.136316.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,613,606 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
1 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/3371962/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-533500-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-533500-G-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-533500-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005343.4%3Ac.403C…
- OncoKB ↗www.oncokb.org/gene/HRAS/R135G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=HRAS+c.403C%3EG
- 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= 1.23946e-06; MAF= 0.00012%, 2/1613606 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09784e-05; MAF= 0.00110%, 1/91088 alleles, homozygotes = 0).
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 (1 clinical laboratory). (ClinVarID = 3371962)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.423. BayesDel score = -0.136316.
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.