11-65862463-G-C

Variant names:

• chr11-65862463-G-C
• rs545500
• NM_025128.5:c.539G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025128.5(MUS81):​c.539G>C​(p.Arg180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,608,124 control chromosomes in the GnomAD database, including 328,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (23487 hom., cov: 33)
  • Exomes 𝑓: 0.64 (304526 hom.)
• Consequence: MUS81 NM_025128.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0270
• Publications: 39 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.316117E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUS81	NM_025128.5	MANE Select	c.539G>C	p.Arg180Pro	missense	Exon 6 of 16	NP_079404.3
	MUS81	NM_001350283.2		c.539G>C	p.Arg180Pro	missense	Exon 6 of 16	NP_001337212.1
	MUS81	NR_146598.2		n.860G>C		non_coding_transcript_exon	Exon 6 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUS81	ENST00000308110.9	TSL:1 MANE Select	c.539G>C	p.Arg180Pro	missense	Exon 6 of 16	ENSP00000307853.4
	MUS81	ENST00000533035.5	TSL:5	c.314G>C	p.Arg105Pro	missense	Exon 6 of 16	ENSP00000432287.1
	MUS81	ENST00000529374.5	TSL:5	c.311G>C	p.Arg104Pro	missense	Exon 5 of 13	ENSP00000434305.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79503 AN: 151634 Hom.: 23492 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.572 AC: 142643 AN: 249492 AF XY: 0.594

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.318

Gnomad FIN exome AF: 0.700

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.638 AC: 929531 AN: 1456372 Hom.: 304526 Cov.: 49 AF XY: 0.641 AC XY: 464462 AN XY: 724354

African (AFR) AF: 0.248 AC: 8261 AN: 33354

American (AMR) AF: 0.377 AC: 16785 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 16557 AN: 26016

East Asian (EAS) AF: 0.323 AC: 12801 AN: 39628

South Asian (SAS) AF: 0.636 AC: 54696 AN: 86002

European-Finnish (FIN) AF: 0.700 AC: 37127 AN: 53032

Middle Eastern (MID) AF: 0.702 AC: 4034 AN: 5748

European-Non Finnish (NFE) AF: 0.670 AC: 742068 AN: 1107960

Other (OTH) AF: 0.619 AC: 37202 AN: 60138

GnomAD4 genome AF: 0.524 AC: 79510 AN: 151752 Hom.: 23487 Cov.: 33 AF XY: 0.527 AC XY: 39042 AN XY: 74130

African (AFR) AF: 0.261 AC: 10799 AN: 41440

American (AMR) AF: 0.469 AC: 7152 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2216 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1632 AN: 5166

South Asian (SAS) AF: 0.621 AC: 2996 AN: 4828

European-Finnish (FIN) AF: 0.703 AC: 7381 AN: 10498

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45429 AN: 67794

Other (OTH) AF: 0.559 AC: 1177 AN: 2106

Alfa AF: 0.614 Hom.: 8165

Bravo AF: 0.492

TwinsUK AF: 0.671 AC: 2489

ALSPAC AF: 0.672 AC: 2591

ESP6500AA AF: 0.255 AC: 1124

ESP6500EA AF: 0.665 AC: 5713

ExAC AF: 0.576 AC: 69877

Asia WGS AF: 0.489 AC: 1703 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.686

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0000073	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.027
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.11
Sift	Benign	0.087	T
Sift4G	Benign	0.066	T
Polyphen		0.68	P
Vest4		0.19
MPC		0.22
ClinPred		0.0055	T
GERP RS		-2.0
PromoterAI		0.00030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.73
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs545500; hg19: chr11-65629934; COSMIC: COSV57258928; COSMIC: COSV57258928;