NM_005343.4:c.-10C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005343.4(HRAS):c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 1,607,530 control chromosomes in the GnomAD database, including 1,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 128 hom., cov: 34)

Exomes 𝑓: 0.047 ( 1832 hom. )

Consequence

HRAS
NM_005343.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -1.01

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: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]

LRRC56 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 11-534332-G-A is Benign according to our data. Variant chr11-534332-G-A is described in ClinVar as [Benign]. Clinvar id is 137556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534332-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HRAS	NM_005343.4 link	c.-10C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.-10C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1	P01112-2
HRAS	NM_005343.4 link	c.-10C>T	5_prime_UTR_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1	P01112-1X5D945
HRAS	NM_176795.5 link	c.-10C>T	5_prime_UTR_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1	P01112-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HRAS	ENST00000311189.8 link	c.-10C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7	P01112-1
HRAS	ENST00000417302.7 link	c.-10C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	5	NM_176795.5	ENSP00000388246.1	P01112-2
HRAS	ENST00000311189.8 link	c.-10C>T	5_prime_UTR_variant	Exon 2 of 6	1	NM_005343.4	ENSP00000309845.7	P01112-1
HRAS	ENST00000417302.7 link	c.-10C>T	5_prime_UTR_variant	Exon 2 of 6	5	NM_176795.5	ENSP00000388246.1	P01112-2

Frequencies

GnomAD3 genomes

AF:

0.0371

AC:

5645

AN:

152194

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0378

Gnomad ASJ

AF:

0.104

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0695

Gnomad FIN

AF:

0.0296

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0464

Gnomad OTH

AF:

0.0498

GnomAD3 exomes

AF:

0.0440

AC:

10833

AN:

246070

Hom.:

338

AF XY:

0.0466

AC XY:

6236

AN XY:

133912

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.0298

Gnomad ASJ exome

AF:

0.0985

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0668

Gnomad FIN exome

AF:

0.0312

Gnomad NFE exome

AF:

0.0504

Gnomad OTH exome

AF:

0.0511

GnomAD4 exome

AF:

0.0467

AC:

67942

AN:

1455218

Hom.:

1832

Cov.:

AF XY:

0.0476

AC XY:

34499

AN XY:

724300

show subpopulations

Gnomad4 AFR exome

AF:

0.0172

Gnomad4 AMR exome

AF:

0.0322

Gnomad4 ASJ exome

AF:

0.0994

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0672

Gnomad4 FIN exome

AF:

0.0313

Gnomad4 NFE exome

AF:

0.0474

Gnomad4 OTH exome

AF:

0.0509

GnomAD4 genome

AF:

0.0370

AC:

5643

AN:

152312

Hom.:

128

Cov.:

AF XY:

0.0365

AC XY:

2719

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0179

Gnomad4 AMR

AF:

0.0377

Gnomad4 ASJ

AF:

0.104

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0694

Gnomad4 FIN

AF:

0.0296

Gnomad4 NFE

AF:

0.0464

Gnomad4 OTH

AF:

0.0492

Alfa

AF:

0.0456

Hom.:

Bravo

AF:

0.0371

Asia WGS

AF:

0.0300

AC:

107

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Jan 24, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

LB/B > 4 on ClinVar or LB/B > 2 Rep -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Costello syndrome

Benign:1

Nov 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome and Noonan-related syndrome

Benign:1

Jun 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.4

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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