rs2075789

Positions:

• chr6-31740551-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_172166.4(MSH5):​c.85C>T​(p.Pro29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,526,338 control chromosomes in the GnomAD database, including 8,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.093 (832 hom., cov: 31)
  • Exomes 𝑓: 0.099 (7777 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0390

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004588902).
• BP6: Variant 6-31740551-C-T is Benign according to our data. Variant chr6-31740551-C-T is described in ClinVar as [Benign]. Clinvar id is 403111.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH5	NM_172166.4	c.85C>T	p.Pro29Ser	missense_variant	2/25	ENST00000375750.9	NP_751898.1
MSH5-SAPCD1	NR_037846.1	n.213C>T		non_coding_transcript_exon_variant	2/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.85C>T	p.Pro29Ser	missense_variant	2/25	1	NM_172166.4	ENSP00000364903	A2

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14131 AN: 152010 Hom.: 830 Cov.: 31

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0775

GnomAD3 exomes AF: 0.126 AC: 15944 AN: 126162 Hom.: 1217 AF XY: 0.123 AC XY: 8464 AN XY: 68762

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0424

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.0954

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0988 AC: 135706 AN: 1374210 Hom.: 7777 Cov.: 31 AF XY: 0.0991 AC XY: 67201 AN XY: 678122

Gnomad4 AFR exome AF: 0.0306

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.0427

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.0900

Gnomad4 OTH exome AF: 0.0974

GnomAD4 genome AF: 0.0930 AC: 14142 AN: 152128 Hom.: 832 Cov.: 31 AF XY: 0.0996 AC XY: 7406 AN XY: 74376

Gnomad4 AFR AF: 0.0350

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.0404

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.0960

Gnomad4 OTH AF: 0.0772

Alfa AF: 0.0916 Hom.: 682

Bravo AF: 0.0890

TwinsUK AF: 0.0912 AC: 338

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.0322 AC: 129

ESP6500EA AF: 0.0830 AC: 669

ExAC AF: 0.0822 AC: 8196

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

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: MAF -

MSH5-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Benign	0.92
DEOGEN2	Benign	0.074	T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;L;L
PROVEAN	Benign	-0.030	N;N;N;N;N
REVEL	Benign	0.057
Sift	Uncertain	0.022	D;D;D;D;D
Sift4G	Benign	0.11	T;T;D;D;D
Polyphen		0.0	B;B;.;B;B
Vest4		0.034
MPC		0.45
ClinPred		0.0040	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.51

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: rs2075789; hg19: chr6-31708328;