rs1802127

chr6-31762148-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.2356C>T(p.Pro786Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0233 in 1,614,030 control chromosomes in the GnomAD database, including 1,098 homozygotes. In-silico tool predicts 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 0.049 (341 hom., cov: 32)
  • Exomes 𝑓: 0.021 (757 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.02

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=0.0015169978).
• BP6: Variant 6-31762148-C-T is Benign according to our data. Variant chr6-31762148-C-T is described in ClinVar as [Benign]. Clinvar id is 3056743.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH5	NM_172166.4	c.2356C>T	p.Pro786Ser	missense_variant	24/25	ENST00000375750.9
MSH5-SAPCD1	NR_037846.1	n.2535C>T		non_coding_transcript_exon_variant	24/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH5	ENST00000375750.9	c.2356C>T	p.Pro786Ser	missense_variant	24/25	1	NM_172166.4	A2

Frequencies

GnomAD3 genomes AF: 0.0491 AC: 7470 AN: 152104 Hom.: 341 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0546

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0703

GnomAD3 exomes AF: 0.0298 AC: 7502 AN: 251442 Hom.: 297 AF XY: 0.0256 AC XY: 3478 AN XY: 135902

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.00421

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0194

Gnomad OTH exome AF: 0.0381

GnomAD4 exome AF: 0.0206 AC: 30176 AN: 1461808 Hom.: 757 Cov.: 32 AF XY: 0.0199 AC XY: 14450 AN XY: 727204

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.00468

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.0165

Gnomad4 OTH exome AF: 0.0322

GnomAD4 genome AF: 0.0492 AC: 7485 AN: 152222 Hom.: 341 Cov.: 32 AF XY: 0.0468 AC XY: 3483 AN XY: 74428

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0696

Alfa AF: 0.0307 Hom.: 288

Bravo AF: 0.0573

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.116 AC: 510

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0289 AC: 3508

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MSH5-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.075	T;T;.;.;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0015	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M;M;.;.;.;.
PROVEAN	Benign	-0.54	N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.19	T;T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;T;T
Polyphen		0.31	B;B;B;B;.;.
Vest4		0.099
MPC		0.59
ClinPred		0.0073	T
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.038
gMVP		0.34

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: rs1802127; hg19: chr6-31729925;