11-65862463-G-C

Position:

• chr11-65862463-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MUS81	NM_025128.5	c.539G>C	p.Arg180Pro	missense_variant	6/16	ENST00000308110.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MUS81	ENST00000308110.9	c.539G>C	p.Arg180Pro	missense_variant	6/16	1	NM_025128.5	P1

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

GnomAD3 exomes AF: 0.572 AC: 142643 AN: 249492 Hom.: 43919 AF XY: 0.594 AC XY: 80131 AN XY: 134954

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 SAS exome AF: 0.634

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

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.636

Gnomad4 EAS exome AF: 0.323

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.700

Gnomad4 NFE exome AF: 0.670

Gnomad4 OTH exome AF: 0.619

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

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.316

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.703

Gnomad4 NFE AF: 0.670

Gnomad4 OTH AF: 0.559

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 v4.3

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;T;T
MetaRNN	Benign	0.0000073	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	.;L;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.087	T;T;T
Sift4G	Benign	0.066	T;T;T
Polyphen		0.68	.;P;.
Vest4		0.19
MPC		0.22
ClinPred		0.0055	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs545500; hg19: chr11-65629934; COSMIC: COSV57258928; COSMIC: COSV57258928;