NM_005591.4:c.154-2114T>C

Variant names:

• chr11-94488198-A-G
• rs2508784
• NM_005591.4:c.154-2114T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005591.4(MRE11):​c.154-2114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 152,040 control chromosomes in the GnomAD database, including 21,253 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.52 (21253 hom., cov: 32)
• Consequence: MRE11 NM_005591.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 3 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRE11	NM_005591.4	c.154-2114T>C		intron_variant	Intron 3 of 19	ENST00000323929.8	NP_005582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRE11	ENST00000323929.8	c.154-2114T>C		intron_variant	Intron 3 of 19	1	NM_005591.4	ENSP00000325863.4

Frequencies

GnomAD3 genomes AF: 0.520 AC: 78975 AN: 151922 Hom.: 21231 Cov.: 32

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.522

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.520 AC: 79046 AN: 152040 Hom.: 21253 Cov.: 32 AF XY: 0.524 AC XY: 38957 AN XY: 74342

African (AFR) AF: 0.660 AC: 27365 AN: 41466

American (AMR) AF: 0.540 AC: 8247 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1557 AN: 3472

East Asian (EAS) AF: 0.491 AC: 2533 AN: 5160

South Asian (SAS) AF: 0.604 AC: 2914 AN: 4828

European-Finnish (FIN) AF: 0.466 AC: 4925 AN: 10564

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30035 AN: 67954

Other (OTH) AF: 0.515 AC: 1087 AN: 2110

Alfa AF: 0.483 Hom.: 2388

Bravo AF: 0.528

Asia WGS AF: 0.531 AC: 1844 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.38
DANN	Benign	0.69
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2508784; hg19: chr11-94221364;