rs121913496

Variant names:

• chr11-533873-C-A
• rs121913496
• NM_005343.4:c.183G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-533873-C-A
• chr11-533873-C-G
• chr11-533873-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001318054.2(HRAS):​c.-137G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HRAS NM_001318054.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.129

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 11-533873-C-A is Pathogenic according to our data. Variant chr11-533873-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376318.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.183G>T	p.Gln61His	missense_variant	Exon 3 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.183G>T	p.Gln61His	missense_variant	Exon 3 of 6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.183G>T	p.Gln61His	missense_variant	Exon 3 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.183G>T	p.Gln61His	missense_variant	Exon 3 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 3 Pathogenic:1

May 22, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The HRAS c.183G>T (p.Gln61His) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant alters a GEF interaction site of conserved H_Ras_like domain and was shown to have a reduced hydrolyzed GTPase activity resulting in a constitutively active protein (Bollag, 1991; Der 1986). The variant of interest is absent from broad control datasets of ExAC or gnomAD (~100996 and 276982 chrs tested, respectively). The variant has not, to our knowledge, been reported as germline mutation in individuals diagnosed with Costello (CS) or Noonan Spectrum Related Disorders (NSRD) via publications and/or reputable databases/clinical diagnostic laboratories. Oncogenic Ras codons 12, 13 and 61 are well known as the primary sites where activating somatic mutations result in a constitutively active protein characterized by a reduced GAP action and/or intrinsic GTPase activity. The p.Gln61His is vastly reported in the literature as a somatic variant, identified in melanoma, metaplastic breast carcinoma, lung cancer, head and neck cancer, and other types of tumors. The c.183G>T was identified in a prenatal sample with negative MCC referred for genetic testing due to abnormal ultrasound finding (cystic hygroma, fetal edema and cardiac defect). Considering all evidence and ACMG guidelines, the variant of interest is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.88	.;D;.;D;D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.53	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.1	M;M;M;M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0080	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.076	B;B;B;B;B
Vest4		0.83
MutPred		0.74		Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);
MVP		0.84
MPC		1.0
ClinPred		0.98	D
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.93

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: rs121913496; hg19: chr11-533873; COSMIC: COSV54236743; COSMIC: COSV54236743;