NM_172166.4:c.813-45G>A

Variant names:

• chr6-31753256-G-A
• rs3131379
• NM_172166.4:c.813-45G>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.813-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,558,426 control chromosomes in the GnomAD database, including 10,108 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 0.077 (559 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9549 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.505
• Publications: 140 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.813-45G>A		intron_variant	Intron 10 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.813-45G>A		intron_variant	Intron 10 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.864-45G>A		intron_variant	Intron 10 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0767 AC: 11663 AN: 152126 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0599

GnomAD2 exomes AF: 0.0645 AC: 14212 AN: 220496 AF XY: 0.0632

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0404

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.0780

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0642

GnomAD4 exome AF: 0.105 AC: 147653 AN: 1406182 Hom.: 9549 Cov.: 32 AF XY: 0.102 AC XY: 70344 AN XY: 691472

African (AFR) AF: 0.0645 AC: 2056 AN: 31890

American (AMR) AF: 0.0252 AC: 987 AN: 39172

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 966 AN: 23278

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38780

South Asian (SAS) AF: 0.00263 AC: 209 AN: 79338

European-Finnish (FIN) AF: 0.0808 AC: 4178 AN: 51726

Middle Eastern (MID) AF: 0.00853 AC: 47 AN: 5508

European-Non Finnish (NFE) AF: 0.124 AC: 133914 AN: 1078634

Other (OTH) AF: 0.0915 AC: 5292 AN: 57856

GnomAD4 genome AF: 0.0766 AC: 11664 AN: 152244 Hom.: 559 Cov.: 32 AF XY: 0.0712 AC XY: 5301 AN XY: 74434

African (AFR) AF: 0.0626 AC: 2601 AN: 41536

American (AMR) AF: 0.0372 AC: 570 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0792 AC: 839 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7314 AN: 68010

Other (OTH) AF: 0.0592 AC: 125 AN: 2110

Alfa AF: 0.0975 Hom.: 4176

Bravo AF: 0.0733

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.5
DANN	Benign	0.67
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3131379; hg19: chr6-31721033;