rs730880462

Positions:

• chr11-533586-G-A
• chr11-533586-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318054.2(HRAS):​c.-3C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000274 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HRAS NM_001318054.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42204088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4	c.317C>T	p.Ser106Leu	missense_variant	4/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.317C>T	p.Ser106Leu	missense_variant	4/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8	c.317C>T	p.Ser106Leu	missense_variant	4/6	1	NM_005343.4	ENSP00000309845.7
HRAS	ENST00000417302.7	c.317C>T	p.Ser106Leu	missense_variant	4/6	5	NM_176795.5	ENSP00000388246.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251380 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461534 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Mar 26, 2023

ClinVar contains an entry for this variant (Variation ID: 409948). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. This variant is present in population databases (rs730880462, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 106 of the HRAS protein (p.Ser106Leu). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.;D;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.034
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.42	T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.96	L;L;L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.081	B;B;B;B;B
Vest4		0.61
MutPred		0.30		Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);
MVP		0.83
MPC		0.90
ClinPred		0.76	D
GERP RS		4.1
Varity_R		0.73
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730880462; hg19: chr11-533586; COSMIC: COSV54239556; COSMIC: COSV54239556;