11-94419683-T-C

Position:

• chr11-94419683-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRE11	NM_005591.4	c.*442A>G		3_prime_UTR_variant	20/20	ENST00000323929.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRE11	ENST00000323929.8	c.*442A>G		3_prime_UTR_variant	20/20	1	NM_005591.4	P3

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

Gnomad4 AFR exome AF: 0.0989

Gnomad4 AMR exome AF: 0.0183

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.00218

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0260

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

Gnomad4 AFR AF: 0.0931

Gnomad4 AMR AF: 0.0173

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.0369

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0160 Hom.: 53

Bravo AF: 0.0383

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1061956; hg19: chr11-94152849;