chr11-94470486-G-C

Position:

chr11-94470486-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005591.4(MRE11):c.1002C>G(p.Ser334Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,612,802 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 43 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 37 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.01

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 (MetaRNN=0.0035775304).

BP6

Variant 11-94470486-G-C is Benign according to our data. Variant chr11-94470486-G-C is described in ClinVar as [Benign]. Clinvar id is 140946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-94470486-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0129 (1955/152130) while in subpopulation AFR AF= 0.0443 (1839/41518). AF 95% confidence interval is 0.0426. There are 43 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4 linkuse as main transcript	c.1002C>G	p.Ser334Arg	missense_variant	9/20	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8 linkuse as main transcript	c.1002C>G	p.Ser334Arg	missense_variant	9/20	1	NM_005591.4	ENSP00000325863	P3	P49959-1
MRE11	ENST00000323977.7 linkuse as main transcript	c.1002C>G	p.Ser334Arg	missense_variant	9/19	1		ENSP00000326094		P49959-2
MRE11	ENST00000407439.7 linkuse as main transcript	c.1011C>G	p.Ser337Arg	missense_variant	9/20	2		ENSP00000385614		P49959-3
MRE11	ENST00000393241.8 linkuse as main transcript	c.1002C>G	p.Ser334Arg	missense_variant	9/20	5		ENSP00000376933	A1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1947

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0442

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00460

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00911

GnomAD3 exomes

AF:

0.00353

AC:

886

AN:

251082

Hom.:

AF XY:

0.00242

AC XY:

329

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.0470

Gnomad AMR exome

AF:

0.00220

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000282

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00139

AC:

2036

AN:

1460672

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

875

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.0450

Gnomad4 AMR exome

AF:

0.00257

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.00317

GnomAD4 genome

AF:

0.0129

AC:

1955

AN:

152130

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

919

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0443

Gnomad4 AMR

AF:

0.00459

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00901

Alfa

AF:

0.000696

Hom.:

Bravo

AF:

0.0146

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0450

AC:

198

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00413

AC:

502

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2016	Variant summary: The MRE11A c.1002C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Ser to Arg. 2/3 in-silico tools predict this variant to be benign (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 502/120966 control chromosomes (8 homozygotes) at a frequency of 0.0041499, which is about 66 times the maximal expected frequency of a pathogenic MRE11A allele (0.0000625), highly suggesting this variant is benign. In addition, one clinical laboratory classified this variant as benign. Taken together, this variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 31, 2019	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2014

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. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Ataxia-telangiectasia-like disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.21

T;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

D;D;D;D

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.14

N;.;N;.

MutationTaster

Benign

0.89

D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.52

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.18

B;.;B;.

Vest4

0.30

MutPred

0.38

.;Gain of catalytic residue at S337 (P = 0.0638);.;.;

MVP

0.76

MPC

0.099

ClinPred

0.0079

GERP RS

4.6

Varity_R

0.24

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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