chr6-31743963-A-G

Variant names:

• chr6-31743963-A-G
• rs147242972
• NM_172166.4:c.475A>G

Variant summary

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

The NM_172166.4(MSH5):​c.475A>G​(p.Met159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M159L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05
• Publications: 0 publications found

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

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=0.21297532).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172166.4. 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
	MSH5	NM_172166.4	MANE Select	c.475A>G	p.Met159Val	missense	Exon 6 of 25	NP_751898.1	O43196-1
	MSH5	NM_172165.4		c.475A>G	p.Met159Val	missense	Exon 6 of 25	NP_751897.1	O43196-2
	MSH5	NM_002441.5		c.475A>G	p.Met159Val	missense	Exon 6 of 25	NP_002432.1	A0A024RCM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	ENST00000375750.9	TSL:1 MANE Select	c.475A>G	p.Met159Val	missense	Exon 6 of 25	ENSP00000364903.3	O43196-1
	MSH5	ENST00000375703.7	TSL:1	c.475A>G	p.Met159Val	missense	Exon 6 of 25	ENSP00000364855.3	O43196-2
	MSH5	ENST00000375755.8	TSL:1	c.475A>G	p.Met159Val	missense	Exon 6 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247920 AF XY: 0.0000148

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461574 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727064

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.052
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.26
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.17	B
Vest4		0.48
MutPred		0.41		Gain of helix (P = 0.0696)
MVP		0.74
MPC		0.45
ClinPred		0.16	T
GERP RS		3.4
PromoterAI		-0.16	Neutral
Varity_R		0.20
gMVP		0.30
Mutation Taster		=85/14	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: rs147242972; hg19: chr6-31711740;