11-94479764-TAA-TAAAAA

Variant names:

• chr11-94479764-T-TAAA
• rs35062043
• NM_005591.4:c.315-6_315-4dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001440460.1(MRE11):​c.315-6_315-4dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000432 in 1,157,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: MRE11 NM_001440460.1 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.660
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440460.1. 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.315-6_315-4dupTTT		splice_region intron	N/A	NP_005582.1
	MRE11	NM_001440460.1		c.315-6_315-4dupTTT		splice_region intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.315-6_315-4dupTTT		splice_region 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.315-4_315-3insTTT		splice_region intron	N/A	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.315-4_315-3insTTT		splice_region intron	N/A	ENSP00000326094.3
	MRE11	ENST00000540013.5	TSL:1	c.315-4_315-3insTTT		splice_region intron	N/A	ENSP00000440986.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000432 AC: 5 AN: 1157388 Hom.: 0 Cov.: 30 AF XY: 0.00000694 AC XY: 4 AN XY: 576068

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

African (AFR) AF: 0.00 AC: 0 AN: 27812

American (AMR) AF: 0.00 AC: 0 AN: 34818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20216

East Asian (EAS) AF: 0.00 AC: 0 AN: 30184

South Asian (SAS) AF: 0.00 AC: 0 AN: 69388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4848

European-Non Finnish (NFE) AF: 0.00000453 AC: 4 AN: 882966

Other (OTH) AF: 0.0000211 AC: 1 AN: 47352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000991898), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35062043; hg19: chr11-94212930;