rs3749953

chr6-31745347-A-G

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH5	NM_172166.4	c.766+28A>G		intron_variant		ENST00000375750.9
MSH5-SAPCD1	NR_037846.1	n.945+28A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH5	ENST00000375750.9	c.766+28A>G		intron_variant		1	NM_172166.4	A2

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

GnomAD3 exomes AF: 0.155 AC: 38219 AN: 247092 Hom.: 3617 AF XY: 0.151 AC XY: 20149 AN XY: 133814

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 SAS exome AF: 0.140

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

Gnomad4 AFR exome AF: 0.0838

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.0422

Gnomad4 EAS exome AF: 0.207

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.124

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

Gnomad4 AFR AF: 0.0957

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.0398

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.328

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.113

Alfa AF: 0.117 Hom.: 1965

Bravo AF: 0.127

Asia WGS AF: 0.186 AC: 644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.9
Dann	Benign	0.72

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: rs3749953; hg19: chr6-31713124;