NM_172166.4:c.1326+36C>A

Variant names:

• chr6-31758911-C-A
• rs707939
• NM_172166.4:c.1326+36C>A

Variant summary

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

The NM_172166.4(MSH5):​c.1326+36C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,564,132 control chromosomes in the GnomAD database, including 89,118 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 0.27 (6781 hom., cov: 32)
  • Exomes 𝑓: 0.33 (82337 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.42
• Publications: 68 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 (EAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.1326+36C>A		intron_variant	Intron 15 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.1326+36C>A		intron_variant	Intron 15 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.1377+36C>A		intron_variant	Intron 15 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40373 AN: 151934 Hom.: 6778 Cov.: 32

Gnomad AFR AF: 0.0609

Gnomad AMI AF: 0.411

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.287

GnomAD2 exomes AF: 0.343 AC: 85522 AN: 249332 AF XY: 0.347

Gnomad AFR exome AF: 0.0532

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.362

Gnomad OTH exome AF: 0.352

GnomAD4 exome AF: 0.335 AC: 472721 AN: 1412080 Hom.: 82337 Cov.: 24 AF XY: 0.338 AC XY: 238182 AN XY: 705398

African (AFR) AF: 0.0490 AC: 1585 AN: 32366

American (AMR) AF: 0.387 AC: 17197 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 13134 AN: 25830

East Asian (EAS) AF: 0.431 AC: 16981 AN: 39434

South Asian (SAS) AF: 0.317 AC: 26964 AN: 85144

European-Finnish (FIN) AF: 0.303 AC: 16152 AN: 53370

Middle Eastern (MID) AF: 0.403 AC: 2247 AN: 5572

European-Non Finnish (NFE) AF: 0.337 AC: 359748 AN: 1067236

Other (OTH) AF: 0.319 AC: 18713 AN: 58702

GnomAD4 genome AF: 0.266 AC: 40379 AN: 152052 Hom.: 6781 Cov.: 32 AF XY: 0.267 AC XY: 19842 AN XY: 74314

African (AFR) AF: 0.0608 AC: 2524 AN: 41516

American (AMR) AF: 0.323 AC: 4936 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1783 AN: 3470

East Asian (EAS) AF: 0.362 AC: 1869 AN: 5158

South Asian (SAS) AF: 0.313 AC: 1508 AN: 4812

European-Finnish (FIN) AF: 0.304 AC: 3206 AN: 10552

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23459 AN: 67960

Other (OTH) AF: 0.286 AC: 598 AN: 2094

Alfa AF: 0.336 Hom.: 42862

Bravo AF: 0.259

Asia WGS AF: 0.305 AC: 1065 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	0.31
DANN	Benign	0.74
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs707939; hg19: chr6-31726688; COSMIC: COSV65212319; COSMIC: COSV65212319;