11-532641-A-C

Variant names:

• chr11-532641-A-C
• rs1851173462
• NM_005343.4:c.565T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005343.4(HRAS):​c.565T>G​(p.Ser189Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23593411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.565T>G	p.Ser189Ala	missense_variant	Exon 5 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.*134T>G		3_prime_UTR_variant	Exon 6 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.565T>G	p.Ser189Ala	missense_variant	Exon 5 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302	c.*134T>G		3_prime_UTR_variant	Exon 6 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Costello syndrome Uncertain:1

Nov 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 189 of the HRAS protein (p.Ser189Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine. This variant has not been reported in the literature in individuals with HRAS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	Benign	0.11
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		0.019	B;B;B
Vest4		0.39
MutPred		0.34		Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);
MVP		0.69
MPC		0.86
ClinPred		0.60	D
GERP RS		3.7
Varity_R		0.29
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1851173462; hg19: chr11-532641;