11-94479764-TAA-TA

Variant names:

• chr11-94479764-TA-T
• rs35062043
• NM_005591.4:c.315-4delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The ENST00000323929.8(MRE11):​c.315-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,240,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (0 hom.)
• Consequence: MRE11 ENST00000323929.8 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.660
• 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: Benign. The variant received -8 ACMG points.

• BP6: Variant 11-94479764-TA-T is Benign according to our data. Variant chr11-94479764-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 140809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.315-4delT		splice_region intron	N/A	NP_005582.1
	MRE11	NM_001440460.1		c.315-4delT		splice_region intron	N/A	NP_001427389.1
	MRE11	NM_001440461.1		c.315-4delT		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.315-4delT		splice_region intron	N/A	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.315-4delT		splice_region intron	N/A	ENSP00000326094.3
	MRE11	ENST00000540013.5	TSL:1	c.315-4delT		splice_region intron	N/A	ENSP00000440986.1

Frequencies

GnomAD3 genomes AF: 0.0000544 AC: 8 AN: 147032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000453

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0104 AC: 1251 AN: 120048 AF XY: 0.0110

Gnomad AFR exome AF: 0.00516

Gnomad AMR exome AF: 0.00749

Gnomad ASJ exome AF: 0.00929

Gnomad EAS exome AF: 0.00699

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00871

GnomAD4 exome AF: 0.00610 AC: 6670 AN: 1093306 Hom.: 0 Cov.: 30 AF XY: 0.00589 AC XY: 3209 AN XY: 544484

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

African (AFR) AF: 0.00442 AC: 118 AN: 26682

American (AMR) AF: 0.00411 AC: 134 AN: 32574

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 66 AN: 19002

East Asian (EAS) AF: 0.00356 AC: 101 AN: 28386

South Asian (SAS) AF: 0.00387 AC: 253 AN: 65394

European-Finnish (FIN) AF: 0.00811 AC: 306 AN: 37738

Middle Eastern (MID) AF: 0.00366 AC: 17 AN: 4650

European-Non Finnish (NFE) AF: 0.00653 AC: 5447 AN: 834298

Other (OTH) AF: 0.00511 AC: 228 AN: 44582

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000544 AC: 8 AN: 147032 Hom.: 0 Cov.: 32 AF XY: 0.0000699 AC XY: 5 AN XY: 71536

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

African (AFR) AF: 0.0000248 AC: 1 AN: 40376

American (AMR) AF: 0.000136 AC: 2 AN: 14666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

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

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

European-Finnish (FIN) AF: 0.000212 AC: 2 AN: 9438

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

European-Non Finnish (NFE) AF: 0.0000453 AC: 3 AN: 66176

Other (OTH) AF: 0.00 AC: 0 AN: 1988

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0158 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ataxia-telangiectasia-like disorder 1 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Ataxia-telangiectasia-like disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs35062043; hg19: chr11-94212930; COSMIC: COSV60574453; COSMIC: COSV60574453;