About HRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
HRAS c.37_39delinsAAA, p.(Gly13Lys)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
The variant results in Gly13Lys, located within the P-loop (HRAS residues 10–17), an approved mutational hotspot and critical functional domain per the RASopathy VCEP supplemental material. The P-loop is essential for GTP binding, and this residue is a statistically significant hotspot in cancerhotspots.org.
PM2Moderate
PM2 · moderate
The variant is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the VCEP requirement for complete absence from all population databases.
PP2Supporting
PP2 · supporting
The RASopathy VCEP states that PP2 is applicable to all RASopathy genes described and curated in the specification. HRAS is a curated RASopathy gene with a low rate of benign missense variation, and missense variants are the primary mechanism of disease (gain-of-function). Although this variant is an indel, it produces a single amino acid substitution (Gly13Lys) consistent with missense-like behavior.
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: PM1 moderate, PM2 moderate, PP2 supporting; combination = 2 moderate + 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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 lies 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.
28 criteria with recorded statuses: 3 met · 19 not met · 0 not assessed · 6 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.37_39delinsAAA (p.Gly13Lys) is an in-frame indel in HRAS exon 2 that substitutes Gly13 with Lys within the highly conserved P-loop GTP-binding domain (residues 10–17).
This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
Gly13 lies in the P-loop, a critical functional domain for GTP binding, which is an approved mutational hotspot domain per the RASopathy VCEP.
The ClinGen RASopathy VCEP designates PP2 as applicable to all RASopathy genes; HRAS has a low rate of benign missense variation and missense variants are the primary disease mechanism.
No functional studies have directly tested G13K. The VCEP-approved RAS Activation Assay for HRAS validated G13C and G13D as pathogenic but did not include G13K.
PVS1, PP4, PP5, and BP6 are designated as Not Applicable by the RASopathy VCEP. PS5 is not defined in the VCEP criteria.
Based on PM1 (Moderate), PM2 (Moderate), and PP2 (Supporting), this variant meets criteria for Likely Pathogenic under the ACMG/AMP 2015 scoring framework.
No criteria match.
Met · 3
PM1 ModerateThe variant results in Gly13Lys, located within the P-loop (HRAS residues 10–17), an approved mutational hotspot and critical functional domain per the RASopathy VCEP supplemental material. The P-loop is essential for GTP binding, and this residue is a statistically significant hotspot in cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- P-loop domain (HRAS 10–17) is an approved VCEP PM1 domain
- Gly13 lies within this domain.
- Statistically significant hotspot at this residue per cancerhotspots.org.
- PM1 applicable at Moderate strength per VCEP specification.
Sources
vcep_alignment_with_pm1_domains_pptxcspec ↗
PM2 ModerateThe variant is completely absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the VCEP requirement for complete absence from all population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0.
Still missing
- Indel calling sensitivity in gnomAD may be reduced compared to SNVs.
Sources
PP2 SupportingThe RASopathy VCEP states that PP2 is applicable to all RASopathy genes described and curated in the specification. HRAS is a curated RASopathy gene with a low rate of benign missense variation, and missense variants are the primary mechanism of disease (gain-of-function). Although this variant is an indel, it produces a single amino acid substitution (Gly13Lys) consistent with missense-like behavior. Details ▾Hide ▴
Evidence considered
- VCEP: PP2 is applicable to all RASopathy genes.
- HRAS has a low rate of benign missense variation
- missense is the primary disease mechanism.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No previously established pathogenic variant resulting in the same amino acid change (Gly13Lys) from a different nucleotide change has been identified. This variant is absent from ClinVar, and no alternative nucleotide change producing G13K is reported. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no known pathogenic G13K from a different nucleotide change exists.
Still missing
- No ClinVar entry for any G13K variant.
Sources
PS2 No de novo occurrence data are available for this variant. The VCEP requires de novo with paternity confirmation (PS2_Strong) or ≥2 independent de novo occurrences (PS2_VeryStrong). Details ▾Hide ▴
Evidence considered
- No de novo data identified in case materials or literature.
Still missing
- No proband or parental data provided.
PS3 The VCEP-approved RAS Activation Assay for HRAS is validated for G13C and G13D (both pathogenic), but G13K was not directly tested in any approved functional study. The assay is approved at PS3_Supporting strength only for directly tested variants. Extrapolation from G13C/D to G13K does not satisfy the variant-specific functional evidence requirement for PS3. Details ▾Hide ▴
Evidence considered
- RAS Activation Assay approved for HRAS at PS3_Supporting with G13C and G13D as pathogenic validation controls
- but G13K was not tested.
Still missing
- No G13K-specific functional data in approved VCEP assays or literature.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No independent proband occurrences have been identified. The VCEP requires ≥1 independent occurrence for PS4_Supporting, ≥3 for moderate, ≥5 for strong. The variant is absent from ClinVar and no case reports were identified. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband occurrences identified.
Still missing
- No clinical case data available.
Sources
PM4 PM4 requires protein length changes due to in-frame deletions/insertions or stop-loss variants. This variant replaces 3 nucleotides with 3 nucleotides (c.37_39delinsAAA), maintaining the reading frame with no gain or loss of amino acid residues. The protein consequence is a single amino acid substitution (Gly13Lys), which does not alter protein length. Details ▾Hide ▴
Evidence considered
- In-frame 3bp→3bp change producing a single amino acid substitution with no length change.
Sources
PM6 No de novo occurrence data, confirmed or assumed, are available for this variant. VCEP requires confirmed de novo without confirmation of maternity for PM6_Moderate or ≥2 independent occurrences for PM6_Strong. Details ▾Hide ▴
Evidence considered
- No de novo data identified.
Still missing
- No proband or parental data available.
PP1 No co-segregation data are available. The VCEP requires at least 3 informative meioses for PP1_Supporting, ≥5 for moderate, ≥7 for strong. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family data provided.
PP3 Computational prediction tools (REVEL, BayesDel) are not applicable to this indel variant. No SpliceAI delta scores are available. The statistical hotspot signal is a population-level observation, not a computational prediction of deleteriousness. No multiple lines of computational evidence support a deleterious effect for this variant type. Details ▾Hide ▴
Evidence considered
- REVEL and BayesDel not applicable (indel).
- SpliceAI: no scores available.
- HCI prior: HRAS not supported.
Still missing
- No in silico prediction tools available for this variant type.
BA1 The VCEP BA1 threshold is allele frequency ≥0.05%. The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the stand-alone benign frequency threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF = 0.0% which is below the 0.05% BA1 threshold.
Sources
BS1 The VCEP BS1 threshold is allele frequency ≥0.025%. The variant is completely absent from all population databases. Does not meet the strong benign frequency threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF = 0.0% which is below the 0.025% BS1 threshold.
Sources
BS2 The VCEP specifies that general population data should not be used for BS2 due to variable expressivity and severity of RASopathies. Application requires >3 instances of well-phenotyped family members. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
- VCEP: general population data should not be used for BS2.
- No well-phenotyped family member data available.
Still missing
- No clinical phenotype data from family members.
Sources
BS3 The VCEP-approved functional studies for HRAS did not test G13K directly. No functional data exist showing that G13K has no damaging effect on protein function. BS3 requires well-established functional studies showing no damaging effect; absence of testing does not satisfy this criterion. Details ▾Hide ▴
Evidence considered
- No G13K-specific functional data showing benign effect.
Still missing
- G13K not tested in any functional study.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4 No segregation data are available to evaluate lack of segregation in affected family members. The VCEP requires only one informative meiosis for BS4 application. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family data provided.
BP1 BP1 applies to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, multi-exon deletion) in genes without established LOF correlation. This variant is an in-frame 3bp→3bp change producing a single amino acid substitution, not a truncating variant. Details ▾Hide ▴
Evidence considered
- Variant is not truncating
- produces in-frame single amino acid substitution Gly13Lys.
Sources
BP2 No evidence of the variant occurring in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant. No phase data are available. Details ▾Hide ▴
Evidence considered
- No trans/cis phase data available.
Still missing
- No phase data or co-occurring variant information.
BP3 BP3 requires an in-frame deletion/insertion in a repetitive region without known function. This variant lies within the P-loop (HRAS residues 10–17), a critical functional domain for GTP binding, which has a well-established known function. The P-loop is not a repetitive region without function. Details ▾Hide ▴
Evidence considered
- P-loop (HRAS 10–17) is a critical functional domain with known GTP-binding function
- not a repetitive region without function.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
BP4 No computational evidence suggests no impact on the gene product. REVEL and BayesDel are not applicable to this indel variant. No SpliceAI delta scores are available. The VCEP requires multiple lines of computational evidence suggesting no impact, which cannot be assessed for this variant type. Details ▾Hide ▴
Evidence considered
- No in silico tools applicable to this indel variant for benign prediction.
- No SpliceAI scores available.
Still missing
- Computational prediction tools not available for indel variants of this type.
BP5 No evidence of an alternate molecular basis for disease has been identified in cases carrying this variant. No clinical case data are available to evaluate this criterion. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular diagnoses in variant carriers.
Still missing
- No clinical case data available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP states that loss of function has not been established as a disease mechanism for HRAS in RASopathies, and PVS1 is explicitly designated as Not Applicable for this VCEP. Details ▾Hide ▴
Evidence considered
- VCEP specification: PVS1 is Not Applicable for HRAS/RASopathy genes
- LOF not a confirmed disease mechanism.
Sources
PM5 N/APM5 applies to novel missense changes at a residue where a different pathogenic missense change has been seen. This variant is an in-frame deletion-insertion (c.37_39delinsAAA), not a missense variant. The PM5 candidate analysis confirms this variant class does not fit the classic same-residue missense PM5 framework. Additionally, the VCEP specifies PM5 should not be used independently with PM1 when the residue is a designated mutational hotspot (Gly13 is in the P-loop hotspot). Details ▾Hide ▴
Evidence considered
- Variant class is indel
- not missense.
- PM5 candidates analysis: not_applicable for non-missense variants.
- VCEP: PM5 should not be used independently with PM1 at designated hotspot residues.
Sources
cspec ↗pm5_candidates
PP4 VCEPPP4 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP. See PS4 for proband counting options. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP6 VCEPBP6 is explicitly designated as Not Applicable by the ClinGen RASopathy VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants that do not impact splicing. This variant changes the amino acid sequence (Gly13Lys) and is not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is not synonymous
- produces a non-synonymous change Gly13Lys.
Sources
Identifiers
- Gene
- HRAS
- Transcript
- NM_005343.4
- Coding (HGVS c.)
- NM_005343.4:c.37_39delinsAAA
- Protein (HGVS p.)
- NP_005334.1:p.(Gly13Lys)
- GRCh38
- chr11:534284 ACC>TTT
- GRCh37
- chr11:534284 ACC>TTT
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational prediction tools (REVEL, BayesDel) are not applicable to this indel variant. No SpliceAI delta scores are available. The statistical hotspot signal is a population-level observation, not a computational prediction of deleteriousness. No multiple lines of computational evidence support a deleterious effect for this variant type. Details ▾Hide ▴
Evidence considered
- REVEL and BayesDel not applicable (indel).
- SpliceAI: no scores available.
- HCI prior: HRAS not supported.
Still missing
- No in silico prediction tools available for this variant type.
BP4 No computational evidence suggests no impact on the gene product. REVEL and BayesDel are not applicable to this indel variant. No SpliceAI delta scores are available. The VCEP requires multiple lines of computational evidence suggesting no impact, which cannot be assessed for this variant type. Details ▾Hide ▴
Evidence considered
- No in silico tools applicable to this indel variant for benign prediction.
- No SpliceAI scores available.
Still missing
- Computational prediction tools not available for indel variants of this type.
BP7 N/ABP7 applies to synonymous (silent) variants or intronic/non-coding variants that do not impact splicing. This variant changes the amino acid sequence (Gly13Lys) and is not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is not synonymous
- produces a non-synonymous change Gly13Lys.
Sources
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_005343.4%3Ac.37_39delinsAAA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-534284-ACC-TTT?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-534284-ACC-TTT?dataset=…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-534284-ACC-TTT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005343.4%3Ac.37_3…
- OncoKB ↗www.oncokb.org/gene/HRAS/G13K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=HRAS+c.37_39delinsAAA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
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 lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.