6-31742911-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_172166.4(MSH5):c.306G>A(p.Thr102=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,612,998 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: MSH5 NM_172166.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77

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:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 6-31742911-G-A is Benign according to our data. Variant chr6-31742911-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 718250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH5	NM_172166.4	c.306G>A	p.Thr102=	synonymous_variant	4/25	ENST00000375750.9
MSH5-SAPCD1	NR_037846.1	n.434G>A		non_coding_transcript_exon_variant	4/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH5	ENST00000375750.9	c.306G>A	p.Thr102=	synonymous_variant	4/25	1	NM_172166.4	A2

Frequencies

GnomAD3 genomes AF: 0.00155 AC: 236 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000835 AC: 206 AN: 246592 Hom.: 0 AF XY: 0.000774 AC XY: 104 AN XY: 134418

Gnomad AFR exome AF: 0.00384

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000659 AC: 963 AN: 1460766 Hom.: 8 Cov.: 31 AF XY: 0.000661 AC XY: 480 AN XY: 726698

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000525

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00162 AC: 246 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74436

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000843 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MSH5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	2.1
Dann	Benign	0.82

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: rs112145890; hg19: chr6-31710688; COSMIC: COSV65210625; COSMIC: COSV65210625;