rs630303

Variant names:

• chr11-65864502-G-A
• rs630303
• NM_025128.5:c.1065G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0300
• Publications: 43 publications found

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUS81	NM_025128.5	c.1065G>A	p.Arg355Arg	synonymous_variant	Exon 11 of 16	ENST00000308110.9	NP_079404.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUS81	ENST00000308110.9	c.1065G>A	p.Arg355Arg	synonymous_variant	Exon 11 of 16	1	NM_025128.5	ENSP00000307853.4

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79956 AN: 151964 Hom.: 23708 Cov.: 32

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

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.: 40 AF XY: 0.641 AC XY: 465843 AN XY: 726666

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

GnomAD4 genome AF: 0.526 AC: 79968 AN: 152082 Hom.: 23703 Cov.: 32 AF XY: 0.529 AC XY: 39331 AN XY: 74354

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

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

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.1
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)

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: rs630303; hg19: chr11-65631973; COSMIC: COSV57259580; COSMIC: COSV57259580;