rs9461718

chr6-31760045-A-Cchr6-31760045-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.1686-45A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,607,274 control chromosomes in the GnomAD database, including 1,399 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 0.041 (189 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1210 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09

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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH5	NM_172166.4	c.1686-45A>C		intron_variant		ENST00000375750.9
MSH5-SAPCD1	NR_037846.1	n.1865-45A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH5	ENST00000375750.9	c.1686-45A>C		intron_variant		1	NM_172166.4	A2

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6312 AN: 152022 Hom.: 190 Cov.: 32

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.0490

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0649

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0508

GnomAD3 exomes AF: 0.0419 AC: 10301 AN: 246078 Hom.: 430 AF XY: 0.0417 AC XY: 5541 AN XY: 132948

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.0484

Gnomad EAS exome AF: 0.144

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.00348

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0327 AC: 47548 AN: 1455134 Hom.: 1210 Cov.: 32 AF XY: 0.0332 AC XY: 23995 AN XY: 723004

Gnomad4 AFR exome AF: 0.0615

Gnomad4 AMR exome AF: 0.0459

Gnomad4 ASJ exome AF: 0.0495

Gnomad4 EAS exome AF: 0.0993

Gnomad4 SAS exome AF: 0.0551

Gnomad4 FIN exome AF: 0.00487

Gnomad4 NFE exome AF: 0.0270

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.0415 AC: 6309 AN: 152140 Hom.: 189 Cov.: 32 AF XY: 0.0422 AC XY: 3140 AN XY: 74372

Gnomad4 AFR AF: 0.0617

Gnomad4 AMR AF: 0.0438

Gnomad4 ASJ AF: 0.0490

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0649

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0508

Alfa AF: 0.0296 Hom.: 72

Bravo AF: 0.0450

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.8
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs9461718; hg19: chr6-31727822; COSMIC: COSV65209519; COSMIC: COSV65209519;