11-94479764-TAA-TAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_005591.4(MRE11):c.315-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0821 in 1,044,184 control chromosomes in the GnomAD database, including 484 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 368 hom., cov: 32)

Exomes 𝑓: 0.088 ( 116 hom. )

Consequence

MRE11
NM_005591.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.660

Publications

9 publications found

Variant links:

COSMIC-nc: COSV100120234

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 -16 ACMG points.

BP6

Variant 11-94479764-T-TA is Benign according to our data. Variant chr11-94479764-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 183762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.13 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.315-4dupT	splice_region intron	N/A	NP_005582.1	P49959-1
MRE11	NM_001440460.1		c.315-4dupT	splice_region intron	N/A	NP_001427389.1
MRE11	NM_001440461.1		c.315-4dupT	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.315-4_315-3insT	splice_region intron	N/A	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7	TSL:1	c.315-4_315-3insT	splice_region intron	N/A	ENSP00000326094.3	P49959-2
MRE11	ENST00000540013.5	TSL:1	c.315-4_315-3insT	splice_region intron	N/A	ENSP00000440986.1	F5GXT0

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

6875

AN:

146940

Hom.:

366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.00111

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.0329

Gnomad EAS

AF:

0.000393

Gnomad SAS

AF:

0.0380

Gnomad FIN

AF:

0.00159

Gnomad MID

AF:

0.0588

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.0528

GnomAD2 exomes

AF:

0.0695

AC:

8348

AN:

120048

AF XY:

0.0701

show subpopulations

Gnomad AFR exome

AF:

0.192

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.110

Gnomad EAS exome

AF:

0.0245

Gnomad FIN exome

AF:

0.0414

Gnomad NFE exome

AF:

0.0402

Gnomad OTH exome

AF:

0.0807

GnomAD4 exome

AF:

0.0879

AC:

78840

AN:

897162

Hom.:

116

Cov.:

AF XY:

0.0872

AC XY:

38501

AN XY:

441334

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.228

AC:

5284

AN:

23170

American (AMR)

AF:

0.0673

AC:

1717

AN:

25510

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

1674

AN:

14242

East Asian (EAS)

AF:

0.0623

AC:

1288

AN:

20660

South Asian (SAS)

AF:

0.112

AC:

5594

AN:

49820

European-Finnish (FIN)

AF:

0.0554

AC:

1725

AN:

31152

Middle Eastern (MID)

AF:

0.133

AC:

537

AN:

4030

European-Non Finnish (NFE)

AF:

0.0827

AC:

57243

AN:

692394

Other (OTH)

AF:

0.104

AC:

3778

AN:

36184

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.302

Heterozygous variant carriers

8642

17285

25927

34570

43212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2466

4932

7398

9864

12330

<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:

0.0468

AC:

6880

AN:

147022

Hom.:

368

Cov.:

AF XY:

0.0460

AC XY:

3291

AN XY:

71590

show subpopulations

African (AFR)

AF:

0.133

AC:

5364

AN:

40438

American (AMR)

AF:

0.0233

AC:

342

AN:

14672

Ashkenazi Jewish (ASJ)

AF:

0.0329

AC:

112

AN:

3406

East Asian (EAS)

AF:

0.000394

AC:

AN:

5080

South Asian (SAS)

AF:

0.0376

AC:

176

AN:

4678

European-Finnish (FIN)

AF:

0.00159

AC:

AN:

9412

Middle Eastern (MID)

AF:

0.0563

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.0113

AC:

747

AN:

66146

Other (OTH)

AF:

0.0523

AC:

105

AN:

2006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

299

597

896

1194

1493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0842

Hom.:

Bravo

AF:

0.0506

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (3)

not provided (2)

not specified (2)

Ataxia-telangiectasia-like disorder (1)

Ataxia-telangiectasia-like disorder 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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