11-534197-C-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.111+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0539 in 1,589,506 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (337 hom., cov: 33)
  • Exomes 𝑓: 0.055 (3120 hom.)
• Consequence: HRAS NM_005343.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.391

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 11-534197-C-T is Benign according to our data. Variant chr11-534197-C-T is described in ClinVar as [Benign]. Clinvar id is 40432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534197-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HRAS	NM_005343.4	c.111+15G>A		intron_variant		ENST00000311189.8
HRAS	NM_176795.5	c.111+15G>A		intron_variant		ENST00000417302.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HRAS	ENST00000311189.8	c.111+15G>A		intron_variant		1	NM_005343.4	P1
HRAS	ENST00000417302.7	c.111+15G>A		intron_variant		5	NM_176795.5

Frequencies

GnomAD3 genomes AF: 0.0478 AC: 7270 AN: 152158 Hom.: 336 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0892

Gnomad FIN AF: 0.0191

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0739 AC: 18380 AN: 248758 Hom.: 1163 AF XY: 0.0709 AC XY: 9574 AN XY: 135030

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.145

Gnomad SAS exome AF: 0.0938

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0699

GnomAD4 exome AF: 0.0546 AC: 78409 AN: 1437228 Hom.: 3120 Cov.: 28 AF XY: 0.0551 AC XY: 39480 AN XY: 716572

Gnomad4 AFR exome AF: 0.00851

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.0411

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0952

Gnomad4 FIN exome AF: 0.0240

Gnomad4 NFE exome AF: 0.0453

Gnomad4 OTH exome AF: 0.0621

GnomAD4 genome AF: 0.0478 AC: 7274 AN: 152278 Hom.: 337 Cov.: 33 AF XY: 0.0500 AC XY: 3725 AN XY: 74454

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.0424

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.0891

Gnomad4 FIN AF: 0.0191

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0478 Hom.: 42

Bravo AF: 0.0543

Asia WGS AF: 0.100 AC: 348 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2019	Variant summary: HRAS c.111+15G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.074 in 248758 control chromosomes, predominantly at a frequency of 0.19 within the Latino subpopulation in the gnomAD database, including 688 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 80000-folds over the estimated maximal expected allele frequency for a pathogenic variant in HRAS causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.111+15G>A in Intron 02 of HRAS: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence and has been identified in 4.1% (291/7016) of European American chromosomes from a b road population by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS; dbSNP rs41258054). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Costello syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.5
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs41258054; hg19: chr11-534197; COSMIC: COSV54242364; COSMIC: COSV54242364;