chr11-533502-G-A

Position:

• chr11-533502-G-A

Variant summary

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

The ENST00000311189.8(HRAS):​c.401C>T​(p.Ala134Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A134T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS ENST00000311189.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.79

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.401C>T	p.Ala134Val	missense_variant	4/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.401C>T	p.Ala134Val	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.401C>T	p.Ala134Val	missense_variant	4/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.401C>T	p.Ala134Val	missense_variant	4/6	5	NM_176795.5	ENSP00000388246

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 11, 2013

The Ala134Val variant in HRAS has not been reported in the literature or in larg e population studies, but has been identified in one affected son and his unaffe cted mother by our laboratory. A different variant causing a change at this sam e residue, Ala134Ser, has been reported in one individual with acute lymphoblast ic leukemia (ALL, COSMIC database), which may suggest that a change at this amin o acid position is not tolerated. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ala1 34Val variant may impact the protein. However, this information is not enough to assume pathogenicity. In summary, additional information is needed to fully ass ess the clinical significance of the Ala134Val variant. -

Costello syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 22, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 134 of the HRAS protein (p.Ala134Val). 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: 45303). 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 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	.;D;.;D;D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.80	P;P;P;P;P
Vest4		0.74
MutPred		0.81		Loss of disorder (P = 0.0938);Loss of disorder (P = 0.0938);Loss of disorder (P = 0.0938);Loss of disorder (P = 0.0938);Loss of disorder (P = 0.0938);
MVP		0.95
MPC		1.9
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517141; hg19: chr11-533502;