Genetic Variant HRAS:p.Gly13Arg (chr11-534286-C-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is The variant received 16 classification points (ACMG Germline Pathogenicity v2019): 16P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_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 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. 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:4

Conservation

PhyloP100: 6.09

Publications

295 publications found

Variant links:

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]

HRAS links:

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

LRRC56 links:

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new If you want to explore the variant's impact on the transcript NM_005343.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 points.

PS3

Well-established functional study supports damaging effect (PS3); 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).; SCV004039160: "At least three publications report experimental evidence evaluating an impact on protein function and functional analysis of HRAS c.37G>C confirmed constitutive activation of the MAPK and PI3KK-Akt signaling pathways (Spoerner_2010, Groesser_2012, Lopes-Ventura_2018)."

PM1

Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).

PM2

Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

PM5

Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.G13D: Pathogenic (ClinVar VariationId 12604, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.G13P: Uncertain_significance (ClinVar VariationId 1677304, 0 stars)

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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

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

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.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Costello syndrome (3)

Epidermal nevus (2)

Nevus sebaceous (2)

cutaneous-skeletal hypophosphatemia syndrome (1)

HRAS-related disorder (1)

Linear nevus sebaceous syndrome (1)

Lip and oral cavity carcinoma (1)

NEVUS SPILUS, SOMATIC (1)

Non-immune hydrops fetalis (1)

Noonan syndrome and Noonan-related syndrome (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

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

2.9

PhyloP100

6.1

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Varity_R

0.94

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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.

Publications

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HRAS p.Gly13Arg

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over