11-94479764-T-TA

Position:

• chr11-94479764-T-TA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.660

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRE11	NM_005591.4	c.315-4dupT		splice_region_variant, intron_variant		ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.315-4dupT		splice_region_variant, intron_variant		1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 6875 AN: 146940 Hom.: 366 Cov.: 32

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

GnomAD4 exome AF: 0.0879 AC: 78840 AN: 897162 Hom.: 116 Cov.: 30 AF XY: 0.0872 AC XY: 38501 AN XY: 441334

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.0673

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0623

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.0554

Gnomad4 NFE exome AF: 0.0827

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.0468 AC: 6880 AN: 147022 Hom.: 368 Cov.: 32 AF XY: 0.0460 AC XY: 3291 AN XY: 71590

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000394

Gnomad4 SAS AF: 0.0376

Gnomad4 FIN AF: 0.00159

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.0523

Bravo AF: 0.0506

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2013	This alteration is classified as likely benign based on a combination of the following: 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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 16, 2023	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2016	Variant summary: The c.315-4dupT variant affects a non-conserved intronic nucleotide. MutationTaster 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 6069/84106 control chromosomes (including 57 homozygotes) from ExAC at a frequency of 0.0721589, which is about 1155 times greater than the maximal expected frequency of a pathogenic allele (0.0000625) in this gene, suggesting this variant is benign. In addition, two clinical laboratory/reputable database have classified this variant as benign/likely benign. Taken together, this variant has been classified as Benign. -

Ataxia-telangiectasia-like disorder 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Jun 08, 2016

- -

Ataxia-telangiectasia-like disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs35062043; hg19: chr11-94212930;