NM_005343.4:c.550T>G

Variant names:

• chr11-532656-A-C
• rs1589789436
• NM_005343.4:c.550T>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BS1_Supporting BS2

The NM_005343.4(HRAS):​c.550T>G​(p.Cys184Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HRAS NM_005343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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_benign. Variant got -1 ACMG points.

• PM1: In a lipid_moiety_binding_region S-(15-deoxy-Delta12,14-prostaglandin J2-9-yl)cysteine; alternate (size 0) in uniprot entity RASH_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000342 (5/1460244) while in subpopulation EAS AF= 0.000126 (5/39696). AF 95% confidence interval is 0.0000491. There are 0 homozygotes in gnomad4_exome. There are 2 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.550T>G	p.Cys184Gly	missense_variant	Exon 5 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.*119T>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.550T>G	p.Cys184Gly	missense_variant	Exon 5 of 6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302	c.*119T>G		3_prime_UTR_variant	Exon 6 of 6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460244 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726490

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome Uncertain:1

Jun 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.65
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.51
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.31	N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.76
MutPred		0.53		Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);
MVP		0.60
MPC		1.2
ClinPred		0.36	T
GERP RS		2.9
Varity_R		0.15
gMVP		0.69

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: rs1589789436; hg19: chr11-532656; COSMIC: COSV105837043; COSMIC: COSV105837043;