chr6-31745347-A-G

Variant names:

• chr6-31745347-A-G
• rs3749953
• NM_172166.4:c.766+28A>G

Variant summary

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

The NM_172166.4(MSH5):​c.766+28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 1,523,596 control chromosomes in the GnomAD database, including 15,566 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1766 hom., cov: 30)
  • Exomes 𝑓: 0.13 (13800 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 33 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	NM_172166.4	MANE Select	c.766+28A>G		intron	N/A	NP_751898.1
	MSH5	NM_172165.4		c.766+28A>G		intron	N/A	NP_751897.1
	MSH5	NM_002441.5		c.766+28A>G		intron	N/A	NP_002432.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	ENST00000375750.9	TSL:1 MANE Select	c.766+28A>G		intron	N/A	ENSP00000364903.3
	MSH5	ENST00000375703.7	TSL:1	c.766+28A>G		intron	N/A	ENSP00000364855.3
	MSH5	ENST00000375755.8	TSL:1	c.766+28A>G		intron	N/A	ENSP00000364908.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20971 AN: 151856 Hom.: 1761 Cov.: 30

Gnomad AFR AF: 0.0955

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.155 AC: 38219 AN: 247092 AF XY: 0.151

Gnomad AFR exome AF: 0.0956

Gnomad AMR exome AF: 0.238

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.137

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.131 AC: 180027 AN: 1371624 Hom.: 13800 Cov.: 22 AF XY: 0.130 AC XY: 89545 AN XY: 686758

African (AFR) AF: 0.0838 AC: 2638 AN: 31490

American (AMR) AF: 0.227 AC: 9871 AN: 43450

Ashkenazi Jewish (ASJ) AF: 0.0422 AC: 1078 AN: 25548

East Asian (EAS) AF: 0.207 AC: 8095 AN: 39194

South Asian (SAS) AF: 0.140 AC: 11766 AN: 83820

European-Finnish (FIN) AF: 0.310 AC: 16498 AN: 53238

Middle Eastern (MID) AF: 0.0719 AC: 402 AN: 5590

European-Non Finnish (NFE) AF: 0.119 AC: 122550 AN: 1032030

Other (OTH) AF: 0.124 AC: 7129 AN: 57264

GnomAD4 genome AF: 0.138 AC: 21001 AN: 151972 Hom.: 1766 Cov.: 30 AF XY: 0.148 AC XY: 10999 AN XY: 74246

African (AFR) AF: 0.0957 AC: 3967 AN: 41472

American (AMR) AF: 0.195 AC: 2968 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3470

East Asian (EAS) AF: 0.151 AC: 783 AN: 5170

South Asian (SAS) AF: 0.147 AC: 709 AN: 4818

European-Finnish (FIN) AF: 0.328 AC: 3451 AN: 10522

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.126 AC: 8592 AN: 67960

Other (OTH) AF: 0.113 AC: 237 AN: 2106

Alfa AF: 0.124 Hom.: 5104

Bravo AF: 0.127

Asia WGS AF: 0.186 AC: 644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.72
PhyloP100		0.061
Mutation Taster		=100/0	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: rs3749953; hg19: chr6-31713124;