11-534313-A-G

Position:

• chr11-534313-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005343.4(HRAS):​c.10T>C​(p.Tyr4His) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,304 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.97

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]

HRAS (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a strand (size 8) in uniprot entity RASH_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.10T>C	p.Tyr4His	missense_variant	2/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.10T>C	p.Tyr4His	missense_variant	2/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.10T>C	p.Tyr4His	missense_variant	2/6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.10T>C	p.Tyr4His	missense_variant	2/6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460304 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2017

Variant summary: The HRAS c.10T>C (p.Tyr4His) variant located within conserved GTP-binding protein domain (via InterPro), however outside of GTP/Mg2+ binding site or GEF functional sites. This change involves the alteration of a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed among 118836 control chromosomes (ExAC). A publication, Milinkovic_2014, cites the variant to have been identified in a Cerebellar glioblastoma tumor, however, it was not verified whether it was a germline or a somatic event. The variant of interest has not been, to our knowledge, reported by clinical diagnostic laboratories or reputable databases. Multiple pathogenic variants affecting codons Gly12_Gly13 have been reported, but variants upstream (before position c.34) have not been reported as pathogenic by any databases/clinical diagnostic laboratories, to date. In addition, both ExAC and gnomAD, report another alteration of the same codon, p.Tyr4Cys, identified in 6/65224 and 7/126246 European chrs tested, respectively. Due to the absence of clinical information and lack of functional studies, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D;.;D;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.5	M;M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.065	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.99	D;D;D;D;D
Vest4		0.26
MutPred		0.60		Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);Gain of disorder (P = 0.0222);
MVP		0.86
MPC		2.4
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.83
gMVP		0.98

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: rs1554885164; hg19: chr11-534313; COSMIC: COSV54239461; COSMIC: COSV54239461;