NM_005591.4:c.*442A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.034 ( 211 hom., cov: 32)

Exomes 𝑓: 0.018 ( 31 hom. )

Consequence

MRE11
NM_005591.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.953

Publications

5 publications found

Variant links:

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

MRE11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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 rank	MANE	Protein	UniProt
MRE11	NM_005591.4 link	c.*442A>G		3_prime_UTR_variant	Exon 20 of 20	ENST00000323929.8	NP_005582.1	P49959-1A0A024R395

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MRE11	ENST00000323929.8 link	c.*442A>G	3_prime_UTR_variant	Exon 20 of 20	1	NM_005591.4	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7 link	c.*442A>G	downstream_gene_variant		1		ENSP00000326094.3	P49959-2
MRE11	ENST00000407439.7 link	c.*442A>G	downstream_gene_variant		2		ENSP00000385614.3	P49959-3
MRE11	ENST00000393241.8 link	c.*442A>G	downstream_gene_variant		5		ENSP00000376933.4	F8W7U8

Frequencies

GnomAD3 genomes

AF:

0.0343

AC:

5213

AN:

152060

Hom.:

209

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.0190

AC XY:

745

AN XY:

39170

show subpopulations

African (AFR)

AF:

0.0989

AC:

387

AN:

3912

American (AMR)

AF:

0.0183

AC:

AN:

2902

Ashkenazi Jewish (ASJ)

AF:

0.0233

AC:

120

AN:

5150

East Asian (EAS)

AF:

0.00218

AC:

AN:

11444

South Asian (SAS)

AF:

0.0288

AC:

AN:

1006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

166

Middle Eastern (MID)

AF:

0.0943

AC:

AN:

488

European-Non Finnish (NFE)

AF:

0.0136

AC:

713

AN:

52448

Other (OTH)

AF:

0.0260

AC:

179

AN:

6882

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0343

AC:

5219

AN:

152178

Hom.:

211

Cov.:

AF XY:

0.0342

AC XY:

2546

AN XY:

74402

show subpopulations

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:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0369

AC:

178

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

713

AN:

67984

Other (OTH)

AF:

0.0392

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

252

505

757

1010

1262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0383

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia-like disorder 1

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.72

(source)

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

Publications

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NM_005591.4:c.*442A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over