rs11964779

Variant names:

• chr6-31743847-A-C
• rs11964779
• NM_172166.4:c.416-57A>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.416-57A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,591,922 control chromosomes in the GnomAD database, including 338 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 0.027 (161 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (177 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.668
• Publications: 6 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=-0.65).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.416-57A>C		intron_variant	Intron 5 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.416-57A>C		intron_variant	Intron 5 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.416-57A>C		intron_variant	Intron 5 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4123 AN: 152090 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.0857

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00540

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.0263

GnomAD4 exome AF: 0.00463 AC: 6667 AN: 1439714 Hom.: 177 AF XY: 0.00422 AC XY: 3014 AN XY: 715046

African (AFR) AF: 0.0886 AC: 2882 AN: 32546

American (AMR) AF: 0.0233 AC: 962 AN: 41352

Ashkenazi Jewish (ASJ) AF: 0.000887 AC: 22 AN: 24794

East Asian (EAS) AF: 0.00692 AC: 273 AN: 39466

South Asian (SAS) AF: 0.00173 AC: 144 AN: 83380

European-Finnish (FIN) AF: 0.000252 AC: 13 AN: 51656

Middle Eastern (MID) AF: 0.0145 AC: 82 AN: 5654

European-Non Finnish (NFE) AF: 0.00155 AC: 1712 AN: 1101412

Other (OTH) AF: 0.00970 AC: 577 AN: 59454

GnomAD4 genome AF: 0.0271 AC: 4124 AN: 152208 Hom.: 161 Cov.: 31 AF XY: 0.0267 AC XY: 1987 AN XY: 74424

African (AFR) AF: 0.0855 AC: 3547 AN: 41498

American (AMR) AF: 0.0195 AC: 298 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5182

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4812

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68018

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0136 Hom.: 185

Bravo AF: 0.0313

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.5
DANN	Benign	0.87
PhyloP100		-0.67
PromoterAI		0.028	Neutral
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: rs11964779; hg19: chr6-31711624;