11-94419683-T-C

Variant names:

• chr11-94419683-T-C
• rs1061956
• NM_005591.4:c.*442A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005591.4(MRE11):​c.*442A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 236,576 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (211 hom., cov: 32)
  • Exomes 𝑓: 0.018 (31 hom.)
• Consequence: MRE11 NM_005591.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.953
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-94419683-T-C is Benign according to our data. Variant chr11-94419683-T-C is described in ClinVar as Benign. ClinVar VariationId is 306485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0907 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.*442A>G		3_prime_UTR	Exon 20 of 20	NP_005582.1
	MRE11	NM_001440460.1		c.*442A>G		3_prime_UTR	Exon 21 of 21	NP_001427389.1
	MRE11	NM_001440461.1		c.*442A>G		3_prime_UTR	Exon 21 of 21	NP_001427390.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRE11	ENST00000323929.8	TSL:1 MANE Select	c.*442A>G		3_prime_UTR	Exon 20 of 20	ENSP00000325863.4
	MRE11	ENST00000323977.7	TSL:1	c.*442A>G		downstream_gene	N/A	ENSP00000326094.3
	MRE11	ENST00000407439.7	TSL:2	c.*442A>G		downstream_gene	N/A	ENSP00000385614.3

Frequencies

GnomAD3 genomes AF: 0.0343 AC: 5213 AN: 152060 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0932

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0396

GnomAD4 exome AF: 0.0184 AC: 1552 AN: 84398 Hom.: 31 Cov.: 0 AF XY: 0.0190 AC XY: 745 AN XY: 39170

African (AFR) AF: 0.0989 AC: 387 AN: 3912

American (AMR) AF: 0.0183 AC: 53 AN: 2902

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 120 AN: 5150

East Asian (EAS) AF: 0.00218 AC: 25 AN: 11444

South Asian (SAS) AF: 0.0288 AC: 29 AN: 1006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 166

Middle Eastern (MID) AF: 0.0943 AC: 46 AN: 488

European-Non Finnish (NFE) AF: 0.0136 AC: 713 AN: 52448

Other (OTH) AF: 0.0260 AC: 179 AN: 6882

GnomAD4 genome AF: 0.0343 AC: 5219 AN: 152178 Hom.: 211 Cov.: 32 AF XY: 0.0342 AC XY: 2546 AN XY: 74402

African (AFR) AF: 0.0931 AC: 3866 AN: 41514

American (AMR) AF: 0.0173 AC: 265 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 67984

Other (OTH) AF: 0.0392 AC: 83 AN: 2116

Alfa AF: 0.0169 Hom.: 72

Bravo AF: 0.0383

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ataxia-telangiectasia-like disorder 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.72
DANN	Benign	0.57
PhyloP100		-0.95

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: rs1061956; hg19: chr11-94152849;