11-94478882-C-T

Variant names:

Variant summary

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

The NM_005591.4(MRE11):c.403-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 1,611,268 control chromosomes in the GnomAD database, including 79,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 6977 hom., cov: 33)

Exomes 𝑓: 0.31 ( 72280 hom. )

Consequence

MRE11
NM_005591.4 splice_region, intron

Scores

Splicing: ADA: 0.0001265

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.42

Variant links:

Genes affected

MRE11 (HGNC:7230): (MRE11 homolog, double strand break repair nuclease) This gene encodes a nuclear protein involved in homologous recombination, telomere length maintenance, and DNA double-strand break repair. By itself, the protein has 3' to 5' exonuclease activity and endonuclease activity. The protein forms a complex with the RAD50 homolog; this complex is required for nonhomologous joining of DNA ends and possesses increased single-stranded DNA endonuclease and 3' to 5' exonuclease activities. In conjunction with a DNA ligase, this protein promotes the joining of noncomplementary ends in vitro using short homologies near the ends of the DNA fragments. This gene has a pseudogene on chromosome 3. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

MRE11 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=-0.86).

BP6

Variant 11-94478882-C-T is Benign according to our data. Variant chr11-94478882-C-T is described in ClinVar as [Benign]. Clinvar id is 129623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-94478882-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.403-6G>A		splice_region_variant, intron_variant	Intron 5 of 19	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8 link	c.403-6G>A		splice_region_variant, intron_variant	Intron 5 of 19	1	NM_005591.4	ENSP00000325863.4		P49959-1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44888

AN:

151914

Hom.:

6979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.206

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.316

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.368

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.334

AC:

83483

AN:

249894

Hom.:

14391

AF XY:

0.333

AC XY:

45014

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.200

Gnomad AMR exome

AF:

0.426

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.398

Gnomad SAS exome

AF:

0.348

Gnomad FIN exome

AF:

0.360

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.311

AC:

454419

AN:

1459236

Hom.:

72280

Cov.:

AF XY:

0.313

AC XY:

227213

AN XY:

726006

show subpopulations

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.422

Gnomad4 ASJ exome

AF:

0.335

Gnomad4 EAS exome

AF:

0.414

Gnomad4 SAS exome

AF:

0.352

Gnomad4 FIN exome

AF:

0.351

Gnomad4 NFE exome

AF:

0.301

Gnomad4 OTH exome

AF:

0.310

GnomAD4 genome

AF:

0.295

AC:

44891

AN:

152032

Hom.:

6977

Cov.:

AF XY:

0.301

AC XY:

22370

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.385

Gnomad4 ASJ

AF:

0.316

Gnomad4 EAS

AF:

0.391

Gnomad4 SAS

AF:

0.355

Gnomad4 FIN

AF:

0.368

Gnomad4 NFE

AF:

0.306

Gnomad4 OTH

AF:

0.319

Alfa

AF:

0.307

Hom.:

5972

Bravo

AF:

0.294

Asia WGS

AF:

0.338

AC:

1176

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.403-6G>A variant affects a non-conserved intronic nucleotide. MutationTaster tool predicts benign outcome for this variant. 5/5 splice-tools in Alamut predict that this variant does not affect normal splicing. This variant is found in 39196/120518 control chromosomes (including 6588 homozygotes) from ExAC at a frequency of 0.3252294, which is about 5204 times greater than the maximal expected frequency of a pathogenic allele (0.0000625), suggesting this variant is a common benign polymorphism. One clinical laboratory has classified this variant as likely benign. Taken together, this variant has been classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Ataxia-telangiectasia-like disorder 1

Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ataxia-telangiectasia-like disorder

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

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

-0.86

CADD

Benign

0.26

DANN

Benign

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.0020

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