11-533545-G-C

Position:

• chr11-533545-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The ENST00000311189.8(HRAS):​c.358C>G​(p.Leu120Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L120L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRAS ENST00000311189.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain GTPase HRas (size 185) in uniprot entity RASH_HUMAN there are 67 pathogenic changes around while only 17 benign (80%) in ENST00000311189.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.358C>G	p.Leu120Val	missense_variant	4/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.358C>G	p.Leu120Val	missense_variant	4/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.358C>G	p.Leu120Val	missense_variant	4/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.358C>G	p.Leu120Val	missense_variant	4/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461544 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Costello syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 12, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 120 of the HRAS protein (p.Leu120Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1024545). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HRAS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;D;D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T;T
Polyphen		0.38	B;B;B;B;B
Vest4		0.82
MutPred		0.87		Gain of catalytic residue at L120 (P = 0.0191);Gain of catalytic residue at L120 (P = 0.0191);Gain of catalytic residue at L120 (P = 0.0191);Gain of catalytic residue at L120 (P = 0.0191);Gain of catalytic residue at L120 (P = 0.0191);
MVP		0.76
MPC		1.3
ClinPred		0.97	D
GERP RS		3.2
Varity_R		0.91
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517139; hg19: chr11-533545; COSMIC: COSV54238775; COSMIC: COSV54238775;