rs35062043

Variant names:

• chr11-94479764-TAA-T
• rs35062043
• NM_005591.4:c.315-5_315-4delTT

Your query was ambiguous. Multiple possible variants found:

• chr11-94479764-TAA-T
• chr11-94479764-TAA-TA
• chr11-94479764-TAA-TAAA
• chr11-94479764-TAA-TAAAA
• chr11-94479764-TAA-TAAAAA

Variant summary

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

The ENST00000323929.8(MRE11):​c.315-5_315-4delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000605 in 1,157,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000060 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRE11 ENST00000323929.8 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 9 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 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323929.8. 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.315-5_315-4delTT		splice_region intron	N/A	NP_005582.1
	MRE11	NM_001440460.1		c.315-5_315-4delTT		splice_region intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.315-5_315-4delTT		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.315-5_315-4delTT		splice_region intron	N/A	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.315-5_315-4delTT		splice_region intron	N/A	ENSP00000326094.3
	MRE11	ENST00000540013.5	TSL:1	c.315-5_315-4delTT		splice_region intron	N/A	ENSP00000440986.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 147110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000333 AC: 4 AN: 120048 AF XY: 0.0000468

Gnomad AFR exome AF: 0.0000973

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000175

Gnomad OTH exome AF: 0.000379

GnomAD4 exome AF: 0.00000605 AC: 7 AN: 1157194 Hom.: 0 AF XY: 0.0000104 AC XY: 6 AN XY: 575986

⚠️ 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: 34816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20214

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 69374

European-Finnish (FIN) AF: 0.0000503 AC: 2 AN: 39784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4846

European-Non Finnish (NFE) AF: 0.00000453 AC: 4 AN: 882820

Other (OTH) AF: 0.0000211 AC: 1 AN: 47342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000540080), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 147110 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71590

African (AFR) AF: 0.00 AC: 0 AN: 40384

American (AMR) AF: 0.00 AC: 0 AN: 14670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3410

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66214

Other (OTH) AF: 0.00 AC: 0 AN: 1992

Alfa AF: 0.0000821 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: -3

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

Other links and lift over

dbSNP: rs35062043; hg19: chr11-94212930; COSMIC: COSV60576373; COSMIC: COSV60576373;