Variant rs28381349 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_172166.4(MSH5):c.253C>T(p.Leu85Phe) variant causes a missense change. The variant allele was found at a frequency of 0.02 in 1,612,082 control chromosomes in the GnomAD database, including 690 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.035 ( 162 hom., cov: 31)

Exomes 𝑓: 0.018 ( 528 hom. )

Consequence

MSH5
NM_172166.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.87

Variant links:

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 links:

MSH5-SAPCD1 (HGNC:):

MSH5-SAPCD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016033947).

BP6

Variant 6-31741268-C-T is Benign according to our data. Variant chr6-31741268-C-T is described in ClinVar as [Benign]. Clinvar id is 3056913.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH5	NM_172166.4 linkuse as main transcript	c.253C>T	p.Leu85Phe	missense_variant	3/25	ENST00000375750.9	NP_751898.1
MSH5-SAPCD1	NR_037846.1 linkuse as main transcript	n.381C>T		non_coding_transcript_exon_variant	3/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9 linkuse as main transcript	c.253C>T	p.Leu85Phe	missense_variant	3/25	1	NM_172166.4	ENSP00000364903	A2	O43196-1

Frequencies

GnomAD3 genomes

AF:

0.0348

AC:

5276

AN:

151606

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0674

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0466

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.00396

Gnomad FIN

AF:

0.00152

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0585

GnomAD3 exomes

AF:

0.0250

AC:

6156

AN:

246592

Hom.:

192

AF XY:

0.0218

AC XY:

2928

AN XY:

134408

show subpopulations

Gnomad AFR exome

AF:

0.0700

Gnomad AMR exome

AF:

0.0479

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.000493

Gnomad SAS exome

AF:

0.00408

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0361

GnomAD4 exome

AF:

0.0185

AC:

26993

AN:

1460360

Hom.:

528

Cov.:

AF XY:

0.0179

AC XY:

13006

AN XY:

726472

show subpopulations

Gnomad4 AFR exome

AF:

0.0688

Gnomad4 AMR exome

AF:

0.0483

Gnomad4 ASJ exome

AF:

0.101

Gnomad4 EAS exome

AF:

0.000529

Gnomad4 SAS exome

AF:

0.00451

Gnomad4 FIN exome

AF:

0.00218

Gnomad4 NFE exome

AF:

0.0156

Gnomad4 OTH exome

AF:

0.0283

GnomAD4 genome

AF:

0.0348

AC:

5285

AN:

151722

Hom.:

162

Cov.:

AF XY:

0.0331

AC XY:

2455

AN XY:

74154

show subpopulations

Gnomad4 AFR

AF:

0.0674

Gnomad4 AMR

AF:

0.0466

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.00213

Gnomad4 SAS

AF:

0.00376

Gnomad4 FIN

AF:

0.00152

Gnomad4 NFE

AF:

0.0182

Gnomad4 OTH

AF:

0.0579

Alfa

AF:

0.0265

Hom.:

192

Bravo

AF:

0.0406

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0161

AC:

ESP6500AA

AF:

0.0685

AC:

207

ESP6500EA

AF:

0.0212

AC:

115

ExAC

AF:

0.0232

AC:

2739

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0231

EpiControl

AF:

0.0239

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MSH5-related disorder

Benign:1

Benign, no assertion criteria provided

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

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.059

T;T;.;.;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.84

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.;L;L

PROVEAN

Benign

2.5

N;N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.90

T;T;T;T;T

Sift4G

Benign

0.35

T;T;D;T;T

Polyphen

0.013

B;B;.;B;B

Vest4

0.11

MPC

0.51

ClinPred

0.018

GERP RS

5.0

Varity_R

0.24

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over