rs3117577

Variant names:

• chr6-31759697-A-G
• rs3117577
• NM_172166.4:c.1496-89A>G

Variant summary

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

The NM_172166.4(MSH5):​c.1496-89A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,467,932 control chromosomes in the GnomAD database, including 9,161 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 0.069 (509 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8652 hom.)
• Consequence: MSH5 NM_172166.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.561
• Publications: 40 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=-0.88).
• 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.1496-89A>G		intron_variant	Intron 17 of 24	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.1496-89A>G		intron_variant	Intron 17 of 24	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.1547-89A>G		intron_variant	Intron 17 of 28	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10564 AN: 152052 Hom.: 509 Cov.: 32

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0319

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0532

GnomAD4 exome AF: 0.101 AC: 133323 AN: 1315762 Hom.: 8652 Cov.: 20 AF XY: 0.0980 AC XY: 64243 AN XY: 655536

African (AFR) AF: 0.0411 AC: 1245 AN: 30310

American (AMR) AF: 0.0231 AC: 931 AN: 40262

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 926 AN: 22682

East Asian (EAS) AF: 0.000103 AC: 4 AN: 38864

South Asian (SAS) AF: 0.000347 AC: 27 AN: 77718

European-Finnish (FIN) AF: 0.0816 AC: 3456 AN: 42328

Middle Eastern (MID) AF: 0.00669 AC: 32 AN: 4786

European-Non Finnish (NFE) AF: 0.121 AC: 121856 AN: 1003642

Other (OTH) AF: 0.0878 AC: 4846 AN: 55170

GnomAD4 genome AF: 0.0694 AC: 10562 AN: 152170 Hom.: 509 Cov.: 32 AF XY: 0.0646 AC XY: 4808 AN XY: 74406

African (AFR) AF: 0.0387 AC: 1608 AN: 41510

American (AMR) AF: 0.0318 AC: 486 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0792 AC: 840 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7309 AN: 67984

Other (OTH) AF: 0.0526 AC: 111 AN: 2110

Alfa AF: 0.0984 Hom.: 3523

Bravo AF: 0.0648

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3117577; hg19: chr6-31727474;