11-534242-A-G

Variant names:

• chr11-534242-A-G
• rs12628
• NM_005343.4:c.81T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005343.4(HRAS):​c.81T>C​(p.His27His) 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
• Clinical Significance: Benign reviewed by expert panel U:1 B:15 O:1
• Conservation: PhyloP100: 1.91
• Publications: 130 publications found

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]

LRRC56 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 39

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 40431.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	NM_005343.4	MANE Select	c.81T>C	p.His27His	synonymous	Exon 2 of 6	NP_005334.1
	HRAS	NM_176795.5	MANE Plus Clinical	c.81T>C	p.His27His	synonymous	Exon 2 of 6	NP_789765.1
	HRAS	NM_001130442.3		c.81T>C	p.His27His	synonymous	Exon 2 of 5	NP_001123914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HRAS	ENST00000311189.8	TSL:1 MANE Select	c.81T>C	p.His27His	synonymous	Exon 2 of 6	ENSP00000309845.7
	HRAS	ENST00000417302.7	TSL:5 MANE Plus Clinical	c.81T>C	p.His27His	synonymous	Exon 2 of 6	ENSP00000388246.1
	HRAS	ENST00000493230.5	TSL:1	n.81T>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000434023.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51764 AN: 151950 Hom.: 9032 Cov.: 33

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

GnomAD2 exomes AF: 0.316 AC: 79100 AN: 250438 AF XY: 0.311

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 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.: 34 AF XY: 0.328 AC XY: 238255 AN XY: 726624

African (AFR) AF: 0.375 AC: 12539 AN: 33454

American (AMR) AF: 0.376 AC: 16833 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 7074 AN: 26124

East Asian (EAS) AF: 0.179 AC: 7114 AN: 39694

South Asian (SAS) AF: 0.254 AC: 21876 AN: 86252

European-Finnish (FIN) AF: 0.278 AC: 14723 AN: 53054

Middle Eastern (MID) AF: 0.270 AC: 1558 AN: 5766

European-Non Finnish (NFE) AF: 0.344 AC: 381912 AN: 1111100

Other (OTH) AF: 0.312 AC: 18834 AN: 60346

GnomAD4 genome AF: 0.341 AC: 51809 AN: 152068 Hom.: 9044 Cov.: 33 AF XY: 0.336 AC XY: 25012 AN XY: 74332

African (AFR) AF: 0.380 AC: 15758 AN: 41486

American (AMR) AF: 0.373 AC: 5704 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 931 AN: 3470

East Asian (EAS) AF: 0.187 AC: 968 AN: 5168

South Asian (SAS) AF: 0.253 AC: 1216 AN: 4814

European-Finnish (FIN) AF: 0.257 AC: 2721 AN: 10592

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23398 AN: 67946

Other (OTH) AF: 0.338 AC: 714 AN: 2110

Alfa AF: 0.341 Hom.: 7725

Bravo AF: 0.348

Asia WGS AF: 0.247 AC: 856 AN: 3476

ClinVar

Significance: Benign

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

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Feb 14, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

Jul 12, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3 Other:1

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32296843, 26607044, 12540507, 21514184, 23150177, 16488657)

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

Costello syndrome Uncertain:1 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RASopathy Benign:2

Baylor Genetics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Variant classified using ACMG guidelines

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vivo

Cardiovascular phenotype Benign:1

Dec 04, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 08, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.7
DANN	Benign	0.82
PhyloP100		1.9
PromoterAI		-0.040	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12628; hg19: chr11-534242; COSMIC: COSV54237196; COSMIC: COSV54237196;