HRAS p.Gly13Arg

Variant names:

• chr11-534286-C-G
• rs104894228
• NM_005343.4:c.37G>C
• HRAS p.Gly13Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-534286-C-G
• chr11-534284-ACC-GCG
• chr11-534284-ACC-TCG
• chr11-534284-ACC-CCG
• chr11-534284-ACC-TCT
• chr11-534284-ACC-CCT

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 26 classification points (ACGS-UK Somatic Oncogenicity v2025): 26P and 0B. O1_Very_StrongO3_ModerateO4_ModerateO5_SupportingO6_SupportingO7_Strong

The NM_005343.4(HRAS):c.37G>C (p.Gly13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene HRAS is a known oncogene (CancerMine: 125 oncogene, 53 driver citations). The gene HRAS is a cancer driver gene (CancerMine: 125 oncogene, 53 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005902203: "functional studies show that this variant results in activation of the Ras-Raf-MAPK and PI3K-Akt signaling pathways with increased cellular proliferation" (Groesser L et al., PMID:22683711)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G13D: Pathogenic (ClinVar VariationId 12604, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G13P: Uncertain_significance (ClinVar VariationId 1677304, 0 stars) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 75 samples carry this exact amino acid change out of 600 samples with a variant at this residue. The variant has been observed in cBioPortal in 146 samples across 57 studies and 38 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 O:4
• Conservation: PhyloP100: 6.09
• Publications: 295 publications found

Genes affected

HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]

LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for HRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 26 points.

• O1: Variant on SVIG-UK Canonical Variants List — Stand-alone Oncogenic (O1); ClinVar oncogenic AND CGI oncogenic — two independent sources, Very Strong (O1); CGI exact DNA-change oncogenic — Strong (O1); O1 contributing sources (16.0 pts): SVIG-UK Canonical Variants List, ClinVar SCI Tier I Strong (★★), CGI (Cancer Genome Interpreter)
• O3: Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
• O4: Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=146 | studies=57 | cancer types=38 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.
• O5: Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: false | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: true | ClinVar diff-AA germline P/LP: true
• O6: Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
• O7: Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 600, same AA change = 75; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.37G>C	p.Gly13Arg	missense	Exon 2 of 6	NP_005334.1	P01112-1
	HRAS	NM_176795.5	MANE Plus Clinical	c.37G>C	p.Gly13Arg	missense	Exon 2 of 6	NP_789765.1	P01112-2
	HRAS	NM_001130442.3		c.37G>C	p.Gly13Arg	missense	Exon 2 of 5	NP_001123914.1	X5D945

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.37G>C	p.Gly13Arg	missense	Exon 2 of 6	ENSP00000309845.7	P01112-1
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.37G>C	p.Gly13Arg	missense	Exon 2 of 6	ENSP00000388246.1	P01112-2
	HRAS	ENST00000493230.5	TSL:1	n.37G>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1	P01112-2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Costello syndrome (3)
2	-	-	Epidermal nevus (2)
2	-	-	Nevus sebaceous (2)
1	-	-	cutaneous-skeletal hypophosphatemia syndrome (1)
1	-	-	HRAS-related disorder (1)
1	-	-	Linear nevus sebaceous syndrome (1)
1	-	-	Lip and oral cavity carcinoma (1)
1	-	-	NEVUS SPILUS, SOMATIC (1)
1	-	-	Non-immune hydrops fetalis (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	SPITZ NEVUS, SOMATIC (1)
-	-	-	Alveolar rhabdomyosarcoma (1)
-	-	-	Breast phyllodes tumor (1)
-	-	-	Ectomesenchymoma (1)
-	-	-	Embryonal rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.94
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104894228;

hg19: chr11-534286;

COSMIC: COSV54236651;

COSMIC: COSV54236651;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar