chr11-65864791-G-T

Variant names:

• chr11-65864791-G-T
• rs558114
• NM_025128.5:c.1248G>T

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.1248G>T​(p.Thr416Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,612,924 control chromosomes in the GnomAD database, including 328,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23672 hom., cov: 33)
  • Exomes 𝑓: 0.64 (304820 hom.)
• Consequence: MUS81 NM_025128.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -9.37

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=0.053).
• BP6: Variant 11-65864791-G-T is Benign according to our data. Variant chr11-65864791-G-T is described in ClinVar as [Benign]. Clinvar id is 402819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.37 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.1248G>T	p.Thr416Thr	synonymous_variant	Exon 12 of 16	ENST00000308110.9	NP_079404.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUS81	ENST00000308110.9	c.1248G>T	p.Thr416Thr	synonymous_variant	Exon 12 of 16	1	NM_025128.5	ENSP00000307853.4

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79843 AN: 151936 Hom.: 23677 Cov.: 33

Gnomad AFR AF: 0.262

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: 0.706

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.573 AC: 143491 AN: 250230 AF XY: 0.595

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.370

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.703

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.619

GnomAD4 exome AF: 0.638 AC: 932128 AN: 1460870 Hom.: 304820 Cov.: 51 AF XY: 0.641 AC XY: 465888 AN XY: 726782

Gnomad4 AFR exome AF: 0.249 AC: 8320 AN: 33470

Gnomad4 AMR exome AF: 0.378 AC: 16905 AN: 44698

Gnomad4 ASJ exome AF: 0.636 AC: 16615 AN: 26126

Gnomad4 EAS exome AF: 0.323 AC: 12839 AN: 39692

Gnomad4 SAS exome AF: 0.636 AC: 54838 AN: 86244

Gnomad4 FIN exome AF: 0.701 AC: 36992 AN: 52808

Gnomad4 NFE exome AF: 0.669 AC: 744237 AN: 1111690

Gnomad4 Remaining exome AF: 0.618 AC: 37332 AN: 60374

GnomAD4 genome AF: 0.525 AC: 79850 AN: 152054 Hom.: 23672 Cov.: 33 AF XY: 0.528 AC XY: 39262 AN XY: 74346

Gnomad4 AFR AF: 0.262 AC: 0.261551 AN: 0.261551

Gnomad4 AMR AF: 0.470 AC: 0.469564 AN: 0.469564

Gnomad4 ASJ AF: 0.639 AC: 0.639273 AN: 0.639273

Gnomad4 EAS AF: 0.317 AC: 0.316847 AN: 0.316847

Gnomad4 SAS AF: 0.620 AC: 0.62039 AN: 0.62039

Gnomad4 FIN AF: 0.706 AC: 0.705782 AN: 0.705782

Gnomad4 NFE AF: 0.671 AC: 0.671117 AN: 0.671117

Gnomad4 OTH AF: 0.559 AC: 0.558824 AN: 0.558824

Alfa AF: 0.619 Hom.: 44140

Bravo AF: 0.492

Asia WGS AF: 0.490 AC: 1705 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.688

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	-0.87
CADD	Benign	0.057
DANN	Benign	0.82
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs558114; hg19: chr11-65632262; COSMIC: COSV57259324; COSMIC: COSV57259324;