rs3115672

Variant names:

• chr6-31760120-C-T
• rs3115672
• NM_172166.4:c.1716C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_172166.4(MSH5):​c.1716C>T​(p.Thr572Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,607,220 control chromosomes in the GnomAD database, including 10,302 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (559 hom., cov: 32)
  • Exomes 𝑓: 0.10 (9743 hom.)
• Consequence: MSH5 NM_172166.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0320
• Publications: 42 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 6-31760120-C-T is Benign according to our data. Variant chr6-31760120-C-T is described in ClinVar as Benign. ClinVar VariationId is 403110.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.032 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.1716C>T	p.Thr572Thr	synonymous_variant	Exon 19 of 25	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.1716C>T	p.Thr572Thr	synonymous_variant	Exon 19 of 25	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.1767C>T		non_coding_transcript_exon_variant	Exon 19 of 29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0766 AC: 11657 AN: 152128 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0788

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0590

GnomAD2 exomes AF: 0.0642 AC: 15692 AN: 244400 AF XY: 0.0625

Gnomad AFR exome AF: 0.0618

Gnomad AMR exome AF: 0.0238

Gnomad ASJ exome AF: 0.0384

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.0784

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0636

GnomAD4 exome AF: 0.104 AC: 151306 AN: 1454974 Hom.: 9743 Cov.: 34 AF XY: 0.100 AC XY: 72696 AN XY: 723488

African (AFR) AF: 0.0646 AC: 2153 AN: 33330

American (AMR) AF: 0.0253 AC: 1111 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.0408 AC: 1042 AN: 25518

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39672

South Asian (SAS) AF: 0.00268 AC: 228 AN: 84996

European-Finnish (FIN) AF: 0.0808 AC: 4297 AN: 53156

Middle Eastern (MID) AF: 0.00854 AC: 49 AN: 5740

European-Non Finnish (NFE) AF: 0.124 AC: 136984 AN: 1108600

Other (OTH) AF: 0.0905 AC: 5438 AN: 60080

GnomAD4 genome AF: 0.0766 AC: 11658 AN: 152246 Hom.: 559 Cov.: 32 AF XY: 0.0712 AC XY: 5296 AN XY: 74430

African (AFR) AF: 0.0626 AC: 2600 AN: 41540

American (AMR) AF: 0.0371 AC: 568 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.0788 AC: 836 AN: 10610

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

European-Non Finnish (NFE) AF: 0.108 AC: 7316 AN: 67998

Other (OTH) AF: 0.0583 AC: 123 AN: 2108

Alfa AF: 0.0988 Hom.: 1931

Bravo AF: 0.0733

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.032
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs3115672; hg19: chr6-31727897; COSMIC: COSV65209698; COSMIC: COSV65209698;