rs1131691997

Variant names:

• chr11-533601-T-A
• NM_005343.4:c.302A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-533601-T-A
• chr11-533601-T-C
• chr11-533601-T-G

Variant summary

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

The NM_005343.4(HRAS):​c.302A>T​(p.Lys101Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 2.69

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 4 ACMG points.

• PM1: In a chain GTPase HRas, N-terminally processed (size 184) in uniprot entity RASH_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_005343.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.302A>T	p.Lys101Ile	missense_variant	Exon 4 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.302A>T	p.Lys101Ile	missense_variant	Exon 4 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.302A>T	p.Lys101Ile	missense_variant	Exon 4 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.302A>T	p.Lys101Ile	missense_variant	Exon 4 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Jul 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K101I variant (also known as c.302A>T), located in coding exon 3 of the HRAS gene, results from an A to T substitution at nucleotide position 302. The lysine at codon 101 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;.;D;D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.069
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.50	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	-0.39	N;N;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Benign	0.091	T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.0020	B;B;B;B;B
Vest4		0.65
MutPred		0.52		Loss of disorder (P = 0.0084);Loss of disorder (P = 0.0084);Loss of disorder (P = 0.0084);Loss of disorder (P = 0.0084);Loss of disorder (P = 0.0084);
MVP		0.79
MPC		1.8
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.78
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-533601;