Genetic Variant MUS81:p.Arg355Arg (chr11-65864502-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_025128.5(MUS81):c.1065G>A(p.Arg355Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 1,612,680 control chromosomes in the GnomAD database, including 328,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 23703 hom., cov: 32)

Exomes 𝑓: 0.64 ( 304880 hom. )

Consequence

MUS81
NM_025128.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0300

Publications

43 publications found

Variant links:

Genes affected

MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

MUS81 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.118).

BP6

Variant 11-65864502-G-A is Benign according to our data. Variant chr11-65864502-G-A is described in ClinVar as Benign. ClinVar VariationId is 402818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025128.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUS81	NM_025128.5	MANE Select	c.1065G>A	p.Arg355Arg	synonymous	Exon 11 of 16	NP_079404.3
MUS81	NM_001350283.2		c.1068G>A	p.Arg356Arg	synonymous	Exon 11 of 16	NP_001337212.1
MUS81	NR_146598.2		n.1386G>A		non_coding_transcript_exon	Exon 11 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MUS81	ENST00000308110.9	TSL:1 MANE Select	c.1065G>A	p.Arg355Arg	synonymous	Exon 11 of 16	ENSP00000307853.4
MUS81	ENST00000533035.5	TSL:5	c.840G>A	p.Arg280Arg	synonymous	Exon 11 of 16	ENSP00000432287.1
MUS81	ENST00000529374.5	TSL:5	c.840G>A	p.Arg280Arg	synonymous	Exon 10 of 13	ENSP00000434305.1

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79956

AN:

151964

Hom.:

23708

Cov.:

show subpopulations

Gnomad AFR

AF:

0.264

Gnomad AMI

AF:

0.586

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.639

Gnomad EAS

AF:

0.317

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.705

Gnomad MID

AF:

0.704

Gnomad NFE

AF:

0.671

Gnomad OTH

AF:

0.560

GnomAD2 exomes

AF:

0.574

AC:

144193

AN:

251210

AF XY:

0.596

show subpopulations

Gnomad AFR exome

AF:

0.254

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.636

Gnomad EAS exome

AF:

0.320

Gnomad FIN exome

AF:

0.702

Gnomad NFE exome

AF:

0.674

Gnomad OTH exome

AF:

0.618

GnomAD4 exome

AF:

0.638

AC:

932091

AN:

1460598

Hom.:

304880

Cov.:

AF XY:

0.641

AC XY:

465843

AN XY:

726666

show subpopulations

African (AFR)

AF:

0.251

AC:

8396

AN:

33458

American (AMR)

AF:

0.379

AC:

16920

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.636

AC:

16618

AN:

26128

East Asian (EAS)

AF:

0.323

AC:

12815

AN:

39682

South Asian (SAS)

AF:

0.636

AC:

54830

AN:

86234

European-Finnish (FIN)

AF:

0.700

AC:

37370

AN:

53348

Middle Eastern (MID)

AF:

0.702

AC:

4048

AN:

5764

European-Non Finnish (NFE)

AF:

0.669

AC:

743763

AN:

1110926

Other (OTH)

AF:

0.619

AC:

37331

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

16005

32010

48014

64019

80024

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18980

37960

56940

75920

94900

<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:

0.526

AC:

79968

AN:

152082

Hom.:

23703

Cov.:

AF XY:

0.529

AC XY:

39331

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.264

AC:

10955

AN:

41478

American (AMR)

AF:

0.470

AC:

7180

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

2217

AN:

3470

East Asian (EAS)

AF:

0.317

AC:

1636

AN:

5168

South Asian (SAS)

AF:

0.620

AC:

2988

AN:

4818

European-Finnish (FIN)

AF:

0.705

AC:

7467

AN:

10584

Middle Eastern (MID)

AF:

0.685

AC:

200

AN:

292

European-Non Finnish (NFE)

AF:

0.671

AC:

45605

AN:

67954

Other (OTH)

AF:

0.560

AC:

1186

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1715

3430

5145

6860

8575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.621

Hom.:

58887

Bravo

AF:

0.492

Asia WGS

AF:

0.490

AC:

1708

AN:

3478

EpiCase

AF:

0.680

EpiControl

AF:

0.690

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

4.1

(source)

DANN

Benign

0.85

PhyloP100

-0.030

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over