NM_172166.4:c.1686-45A>C

Variant names:

• chr6-31760045-A-C
• rs9461718
• NM_172166.4:c.1686-45A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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=-0.81).
• 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 rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.1686-45A>C		intron_variant	Intron 18 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.1686-45A>C		intron_variant	Intron 18 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.1737-45A>C		intron_variant	Intron 18 of 28	1		ENSP00000417871.2

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

GnomAD2 exomes AF: 0.0419 AC: 10301 AN: 246078 AF XY: 0.0417

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 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

African (AFR) AF: 0.0615 AC: 2050 AN: 33342

American (AMR) AF: 0.0459 AC: 2036 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.0495 AC: 1269 AN: 25616

East Asian (EAS) AF: 0.0993 AC: 3931 AN: 39588

South Asian (SAS) AF: 0.0551 AC: 4719 AN: 85582

European-Finnish (FIN) AF: 0.00487 AC: 259 AN: 53220

Middle Eastern (MID) AF: 0.115 AC: 660 AN: 5734

European-Non Finnish (NFE) AF: 0.0270 AC: 29944 AN: 1107572

Other (OTH) AF: 0.0446 AC: 2680 AN: 60084

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

African (AFR) AF: 0.0617 AC: 2558 AN: 41492

American (AMR) AF: 0.0438 AC: 669 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 170 AN: 3466

East Asian (EAS) AF: 0.132 AC: 682 AN: 5174

South Asian (SAS) AF: 0.0649 AC: 313 AN: 4820

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1726 AN: 67990

Other (OTH) AF: 0.0508 AC: 107 AN: 2108

Alfa AF: 0.0314 Hom.: 261

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
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9461718; hg19: chr6-31727822; COSMIC: COSV65209519; COSMIC: COSV65209519;