chr11-532655-C-G

Position:

• chr11-532655-C-G

Variant summary

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

The ENST00000311189.8(HRAS):​c.551G>C​(p.Cys184Ser) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C184Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS ENST00000311189.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Loss of S-(15-deoxy-Delta12,14-prostaglandin J2-9-yl)cysteine stimulation of Ras-GTPase activity. Mainly localized in Golgi. Non-specifically localized on all endomembranes; when associated with S-181. (size 0) in uniprot entity RASH_HUMAN
• 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.551G>C	p.Cys184Ser	missense_variant	5/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.*120G>C		3_prime_UTR_variant	6/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.551G>C	p.Cys184Ser	missense_variant	5/6	1	NM_005343.4	ENSP00000309845	P1
HRAS	ENST00000417302.7	c.*120G>C		3_prime_UTR_variant	6/6	5	NM_176795.5	ENSP00000388246

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2021

This sequence change replaces cysteine with serine at codon 184 of the HRAS protein (p.Cys184Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. 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. Experimental studies have shown that this missense change affects HRAS protein function (PMID: 15491620, 23412389, 23548900, 27468687, 28179458). 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. This variant has not been reported in the literature in individuals affected with HRAS-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Benign	0.68
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.57
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.59	N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.72
MutPred		0.49		Gain of disorder (P = 0.0031);Gain of disorder (P = 0.0031);Gain of disorder (P = 0.0031);
MVP		0.69
MPC		1.2
ClinPred		0.21	T
GERP RS		3.1
Varity_R		0.16
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-532655;