11-65862035-G-T

Variant names:

• chr11-65862035-G-T
• rs779669908
• NM_025128.5:c.440G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025128.5(MUS81):​c.440G>T​(p.Arg147Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000756 in 1,455,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R147Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: MUS81 NM_025128.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• Publications: 0 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]

CFL1 (HGNC:1874): (cofilin 1) The protein encoded by this gene can polymerize and depolymerize F-actin and G-actin in a pH-dependent manner. Increased phosphorylation of this protein by LIM kinase aids in Rho-induced reorganization of the actin cytoskeleton. Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12651104).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUS81	NM_025128.5	MANE Select	c.440G>T	p.Arg147Leu	missense	Exon 4 of 16	NP_079404.3
	MUS81	NM_001350283.2		c.440G>T	p.Arg147Leu	missense	Exon 4 of 16	NP_001337212.1
	MUS81	NR_146598.2		n.761G>T		non_coding_transcript_exon	Exon 4 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MUS81	ENST00000308110.9	TSL:1 MANE Select	c.440G>T	p.Arg147Leu	missense	Exon 4 of 16	ENSP00000307853.4	Q96NY9
	MUS81	ENST00000907324.1		c.440G>T	p.Arg147Leu	missense	Exon 6 of 18	ENSP00000577383.1
	MUS81	ENST00000971503.1		c.440G>T	p.Arg147Leu	missense	Exon 5 of 17	ENSP00000641562.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235694 AF XY: 0.00000782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000756 AC: 11 AN: 1455772 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 4 AN XY: 723854

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.00 AC: 0 AN: 85444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1109500

Other (OTH) AF: 0.00 AC: 0 AN: 60140

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.46
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.088
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.011	D
Polyphen		0.63	P
Vest4		0.38
MutPred		0.52		Loss of MoRF binding (P = 0.0325)
MVP		0.36
MPC		0.18
ClinPred		0.47	T
GERP RS		-4.7
PromoterAI		0.0024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.51
Mutation Taster		=64/36	polymorphism

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: rs779669908; hg19: chr11-65629506;