6-31761582-A-G

Variant names:

• chr6-31761582-A-G
• rs707938
• NM_172166.4:c.2148A>G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_172166.4(MSH5):​c.2148A>G​(p.Gln716Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,718 control chromosomes in the GnomAD database, including 106,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (15883 hom., cov: 33)
  • Exomes 𝑓: 0.34 (90547 hom.)
• Consequence: MSH5 NM_172166.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.419

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

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-31761582-A-G is Benign according to our data. Variant chr6-31761582-A-G is described in ClinVar as [Benign]. Clinvar id is 403112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.419 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH5	NM_172166.4	c.2148A>G	p.Gln716Gln	synonymous_variant	Exon 22 of 25	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.2148A>G	p.Gln716Gln	synonymous_variant	Exon 22 of 25	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.2199A>G		non_coding_transcript_exon_variant	Exon 22 of 29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65835 AN: 151992 Hom.: 15848 Cov.: 33

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.427

GnomAD3 exomes AF: 0.382 AC: 95769 AN: 250692 Hom.: 19610 AF XY: 0.379 AC XY: 51357 AN XY: 135678

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.306

Gnomad EAS exome AF: 0.335

Gnomad SAS exome AF: 0.476

Gnomad FIN exome AF: 0.427

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.344 AC: 503039 AN: 1461606 Hom.: 90547 Cov.: 66 AF XY: 0.346 AC XY: 251597 AN XY: 727108

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.433 AC: 65921 AN: 152112 Hom.: 15883 Cov.: 33 AF XY: 0.437 AC XY: 32523 AN XY: 74368

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.308

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.430

Alfa AF: 0.334 Hom.: 18002

Bravo AF: 0.437

Asia WGS AF: 0.515 AC: 1787 AN: 3478

EpiCase AF: 0.299

EpiControl AF: 0.303

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	-0.49
CADD	Benign	9.4
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs707938; hg19: chr6-31729359; COSMIC: COSV65172660; COSMIC: COSV65172660;