11-94478882-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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:12

Conservation

PhyloP100: -2.42

Publications

54 publications found

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 Gene-Disease associations (from GenCC):

ataxia-telangiectasia-like disorder 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
prostate cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 129623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005591.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRE11	NM_005591.4	MANE Select	c.403-6G>A	splice_region intron	N/A	NP_005582.1	P49959-1
MRE11	NM_001440460.1		c.403-6G>A	splice_region intron	N/A	NP_001427389.1
MRE11	NM_001440461.1		c.403-6G>A	splice_region intron	N/A	NP_001427390.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRE11	ENST00000323929.8	TSL:1 MANE Select	c.403-6G>A	splice_region intron	N/A	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7	TSL:1	c.403-6G>A	splice_region intron	N/A	ENSP00000326094.3	P49959-2
MRE11	ENST00000540013.5	TSL:1	c.403-6G>A	splice_region intron	N/A	ENSP00000440986.1	F5GXT0

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

GnomAD2 exomes

AF:

0.334

AC:

83483

AN:

249894

AF XY:

0.333

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 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

African (AFR)

AF:

0.209

AC:

6998

AN:

33424

American (AMR)

AF:

0.422

AC:

18859

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

8739

AN:

26104

East Asian (EAS)

AF:

0.414

AC:

16415

AN:

39606

South Asian (SAS)

AF:

0.352

AC:

30370

AN:

86200

European-Finnish (FIN)

AF:

0.351

AC:

18632

AN:

53018

Middle Eastern (MID)

AF:

0.348

AC:

2003

AN:

5758

European-Non Finnish (NFE)

AF:

0.301

AC:

333729

AN:

1110172

Other (OTH)

AF:

0.310

AC:

18674

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

15627

31254

46881

62508

78135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11052

22104

33156

44208

55260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.295

AC:

44891

AN:

152032

Hom.:

6977

Cov.:

AF XY:

0.301

AC XY:

22370

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.206

AC:

8539

AN:

41494

American (AMR)

AF:

0.385

AC:

5875

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.316

AC:

1096

AN:

3470

East Asian (EAS)

AF:

0.391

AC:

2017

AN:

5158

South Asian (SAS)

AF:

0.355

AC:

1715

AN:

4828

European-Finnish (FIN)

AF:

0.368

AC:

3880

AN:

10544

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.306

AC:

20787

AN:

67944

Other (OTH)

AF:

0.319

AC:

673

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1634

3268

4901

6535

8169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.307

Hom.:

10810

Bravo

AF:

0.294

Asia WGS

AF:

0.338

AC:

1176

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Ataxia-telangiectasia-like disorder 1 (2)

Ataxia-telangiectasia-like disorder (1)

Hereditary breast ovarian cancer syndrome (1)

Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.26

(source)

DANN

Benign

0.40

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over