NM_172166.4:c.253C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

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

Publications

20 publications found

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: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]

MSH5-SAPCD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH5	NM_172166.4	MANE Select	c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	NP_751898.1	O43196-1
MSH5	NM_172165.4		c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	NP_751897.1	O43196-2
MSH5	NM_002441.5		c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	NP_002432.1	A0A024RCM1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MSH5	ENST00000375750.9	TSL:1 MANE Select	c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	ENSP00000364903.3	O43196-1
MSH5	ENST00000375703.7	TSL:1	c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	ENSP00000364855.3	O43196-2
MSH5	ENST00000375755.8	TSL:1	c.253C>T	p.Leu85Phe	missense	Exon 3 of 25	ENSP00000364908.3	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

GnomAD2 exomes

AF:

0.0250

AC:

6156

AN:

246592

AF XY:

0.0218

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 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

African (AFR)

AF:

0.0688

AC:

2302

AN:

33470

American (AMR)

AF:

0.0483

AC:

2160

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2648

AN:

26110

East Asian (EAS)

AF:

0.000529

AC:

AN:

39686

South Asian (SAS)

AF:

0.00451

AC:

389

AN:

86252

European-Finnish (FIN)

AF:

0.00218

AC:

114

AN:

52280

Middle Eastern (MID)

AF:

0.0453

AC:

261

AN:

5760

European-Non Finnish (NFE)

AF:

0.0156

AC:

17391

AN:

1111728

Other (OTH)

AF:

0.0283

AC:

1707

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1288

2576

3863

5151

6439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

684

1368

2052

2736

3420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0348

AC:

5285

AN:

151722

Hom.:

162

Cov.:

AF XY:

0.0331

AC XY:

2455

AN XY:

74154

show subpopulations

African (AFR)

AF:

0.0674

AC:

2789

AN:

41360

American (AMR)

AF:

0.0466

AC:

709

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

362

AN:

3458

East Asian (EAS)

AF:

0.00213

AC:

AN:

5160

South Asian (SAS)

AF:

0.00376

AC:

AN:

4788

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1239

AN:

67920

Other (OTH)

AF:

0.0579

AC:

122

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

247

495

742

990

1237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0269

Hom.:

381

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

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

MSH5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.059

Eigen

Benign

-0.080

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.84

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

3.9

PROVEAN

Benign

2.5

REVEL

Benign

0.058

Sift

Benign

0.90

Sift4G

Benign

0.35

Polyphen

0.013

Vest4

0.11

MPC

0.51

ClinPred

0.018

GERP RS

5.0

Varity_R

0.24

gMVP

0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over