rs1270146

Variant names:

• chr11-94482140-T-C
• rs1270146
• NM_005591.4:c.315-2379A>G

Variant summary

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

The NM_005591.4(MRE11):​c.315-2379A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.514 in 152,042 control chromosomes in the GnomAD database, including 20,672 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 0.51 (20672 hom., cov: 32)
• Consequence: MRE11 NM_005591.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06
• Publications: 7 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.634 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	NM_005591.4	MANE Select	c.315-2379A>G		intron	N/A	NP_005582.1
	MRE11	NM_001440460.1		c.315-2379A>G		intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.315-2379A>G		intron	N/A	NP_001427390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.315-2379A>G		intron	N/A	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.315-2379A>G		intron	N/A	ENSP00000326094.3
	MRE11	ENST00000540013.5	TSL:1	c.315-2379A>G		intron	N/A	ENSP00000440986.1

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78063 AN: 151924 Hom.: 20651 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.493

Gnomad SAS AF: 0.603

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.517

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

GnomAD4 genome AF: 0.514 AC: 78132 AN: 152042 Hom.: 20672 Cov.: 32 AF XY: 0.518 AC XY: 38494 AN XY: 74316

African (AFR) AF: 0.640 AC: 26531 AN: 41452

American (AMR) AF: 0.537 AC: 8209 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1530 AN: 3468

East Asian (EAS) AF: 0.491 AC: 2542 AN: 5172

South Asian (SAS) AF: 0.604 AC: 2915 AN: 4826

European-Finnish (FIN) AF: 0.466 AC: 4928 AN: 10574

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.442 AC: 30017 AN: 67948

Other (OTH) AF: 0.511 AC: 1079 AN: 2112

Alfa AF: 0.469 Hom.: 9083

Bravo AF: 0.521

Asia WGS AF: 0.534 AC: 1855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.092
DANN	Benign	0.19
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1270146; hg19: chr11-94215306;