rs375261439

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_005591.4(MRE11):c.1462C>T(p.Arg488Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

MRE11
NM_005591.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 3.38

Publications

8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
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: Uncertain_significance. The variant received 0 ACMG points.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRE11	NM_005591.4	MANE Select	c.1462C>T	p.Arg488Cys	missense	Exon 13 of 20	NP_005582.1	P49959-1
MRE11	NM_001440460.1		c.1462C>T	p.Arg488Cys	missense	Exon 13 of 21	NP_001427389.1
MRE11	NM_001440461.1		c.1462C>T	p.Arg488Cys	missense	Exon 13 of 21	NP_001427390.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MRE11	ENST00000323929.8	TSL:1 MANE Select	c.1462C>T	p.Arg488Cys	missense	Exon 13 of 20	ENSP00000325863.4	P49959-1
MRE11	ENST00000323977.7	TSL:1	c.1462C>T	p.Arg488Cys	missense	Exon 13 of 19	ENSP00000326094.3	P49959-2
MRE11	ENST00000936196.1		c.1462C>T	p.Arg488Cys	missense	Exon 13 of 21	ENSP00000606255.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251380

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000677

AC:

AN:

1461710

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.000134

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.000151

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000702

AC:

AN:

1111900

Other (OTH)

AF:

0.000132

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41528

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000926

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia-like disorder 1 (3)

Hereditary cancer-predisposing syndrome (2)

Ataxia-telangiectasia-like disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.74

MetaSVM

Uncertain

0.0078

MutationAssessor

Uncertain

2.6

PhyloP100

3.4

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.49

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.92

MVP

0.84

MPC

0.47

ClinPred

0.86

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.44

gMVP

0.39

Mutation Taster

=41/59

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over