rs41294870

Variant names:

• chr11-534332-G-A
• rs41294870
• NM_005343.4:c.-10C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-534332-G-A
• chr11-534332-G-C
• chr11-534332-G-T

Variant summary

Our verdict is Benign. The variant received -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 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: -1.01
• Publications: 15 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 -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 VariationId is 137556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HRAS	NM_005343.4	c.-10C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-10C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1
HRAS	NM_005343.4	c.-10C>T		5_prime_UTR_variant	Exon 2 of 6	ENST00000311189.8	NP_005334.1
HRAS	NM_176795.5	c.-10C>T		5_prime_UTR_variant	Exon 2 of 6	ENST00000417302.7	NP_789765.1

Ensembl

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

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

GnomAD2 exomes AF: 0.0440 AC: 10833 AN: 246070 AF XY: 0.0466

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 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

African (AFR) AF: 0.0172 AC: 575 AN: 33396

American (AMR) AF: 0.0322 AC: 1441 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 2595 AN: 26110

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39678

South Asian (SAS) AF: 0.0672 AC: 5793 AN: 86160

European-Finnish (FIN) AF: 0.0313 AC: 1560 AN: 49840

Middle Eastern (MID) AF: 0.0606 AC: 348 AN: 5746

European-Non Finnish (NFE) AF: 0.0474 AC: 52557 AN: 1109348

Other (OTH) AF: 0.0509 AC: 3068 AN: 60250

GnomAD4 genome AF: 0.0370 AC: 5643 AN: 152312 Hom.: 128 Cov.: 34 AF XY: 0.0365 AC XY: 2719 AN XY: 74474

African (AFR) AF: 0.0179 AC: 743 AN: 41574

American (AMR) AF: 0.0377 AC: 578 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 361 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4828

European-Finnish (FIN) AF: 0.0296 AC: 315 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0464 AC: 3156 AN: 68002

Other (OTH) AF: 0.0492 AC: 104 AN: 2112

Alfa AF: 0.0457 Hom.: 130

Bravo AF: 0.0371

Asia WGS AF: 0.0300 AC: 107 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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 -

-

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

- -

May 29, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

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

- -

-

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. -

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
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs41294870; hg19: chr11-534332; COSMIC: COSV54240784;