rs41294870

chr11-534332-G-Achr11-534332-G-Cchr11-534332-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005343.4(HRAS):c.-10C>T variant causes a 5 prime UTR 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -1.01

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:):

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.-10C>T		5_prime_UTR_variant	2/6	ENST00000311189.8
HRAS	NM_176795.5	c.-10C>T		5_prime_UTR_variant	2/6	ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.-10C>T		5_prime_UTR_variant	2/6	1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.-10C>T		5_prime_UTR_variant	2/6	5	NM_176795.5

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5645 AN: 152194 Hom.: 129 Cov.: 34

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

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.: 32 AF XY: 0.0476 AC XY: 34499 AN XY: 724300

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.: 34 AF XY: 0.0365 AC XY: 2719 AN XY: 74474

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.: 88

Bravo AF: 0.0371

Asia WGS AF: 0.0300 AC: 107 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	LB/B > 4 on ClinVar or LB/B > 2 Rep -
Benign, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 29, 2007	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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:1 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 16, 2021

- -

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

Other links and lift over

dbSNP: rs41294870; hg19: chr11-534332; COSMIC: COSV54240784; COSMIC: COSV54240784;