rs12628

Positions:

chr11-534242-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005343.4(HRAS):c.81T>C(p.His27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,612,572 control chromosomes in the GnomAD database, including 90,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.34 ( 9044 hom., cov: 33)

Exomes 𝑓: 0.33 ( 81035 hom. )

Consequence

HRAS
NM_005343.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:15O:1

Conservation

PhyloP100: 1.91

Variant links:

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]

HRAS links:

LRRC56 (HGNC:):

LRRC56 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 11-534242-A-G is Benign according to our data. Variant chr11-534242-A-G is described in ClinVar as [Benign]. Clinvar id is 40431.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-534242-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.91 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HRAS	NM_005343.4 linkuse as main transcript	c.81T>C	p.His27=	synonymous_variant	2/6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5 linkuse as main transcript	c.81T>C	p.His27=	synonymous_variant	2/6	ENST00000417302.7	NP_789765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HRAS	ENST00000311189.8 linkuse as main transcript	c.81T>C	p.His27=	synonymous_variant	2/6	1	NM_005343.4	ENSP00000309845	P1	P01112-1
HRAS	ENST00000417302.7 linkuse as main transcript	c.81T>C	p.His27=	synonymous_variant	2/6	5	NM_176795.5	ENSP00000388246		P01112-2

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51764

AN:

151950

Hom.:

9032

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.353

Gnomad AMR

AF:

0.373

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.187

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.335

GnomAD3 exomes

AF:

0.316

AC:

79100

AN:

250438

Hom.:

12979

AF XY:

0.311

AC XY:

42242

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.381

Gnomad AMR exome

AF:

0.381

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.187

Gnomad SAS exome

AF:

0.252

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.339

Gnomad OTH exome

AF:

0.311

GnomAD4 exome

AF:

0.330

AC:

482463

AN:

1460504

Hom.:

81035

Cov.:

AF XY:

0.328

AC XY:

238255

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.375

Gnomad4 AMR exome

AF:

0.376

Gnomad4 ASJ exome

AF:

0.271

Gnomad4 EAS exome

AF:

0.179

Gnomad4 SAS exome

AF:

0.254

Gnomad4 FIN exome

AF:

0.278

Gnomad4 NFE exome

AF:

0.344

Gnomad4 OTH exome

AF:

0.312

GnomAD4 genome

AF:

0.341

AC:

51809

AN:

152068

Hom.:

9044

Cov.:

AF XY:

0.336

AC XY:

25012

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.380

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.268

Gnomad4 EAS

AF:

0.187

Gnomad4 SAS

AF:

0.253

Gnomad4 FIN

AF:

0.257

Gnomad4 NFE

AF:

0.344

Gnomad4 OTH

AF:

0.338

Alfa

AF:

0.343

Hom.:

5599

Bravo

AF:

0.348

Asia WGS

AF:

0.247

AC:

856

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 12, 2007	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32296843, 26607044, 12540507, 21514184, 23150177, 16488657) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Costello syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

RASopathy

Benign:2

Benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.81T>C (p.His27=) variant in the HRAS gene is 36.7% for African chromosomes by the Exome Aggregation Consortium (3874/10274 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additional case-level data provided by: SCV000058315; SCV000062146; SCV000196686. -

Squamous cell lung carcinoma

Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.7

DANN

Benign

0.82

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over