Genetic Variant MSH5:p.Thr102Thr (chr6-31742911-G-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_172166.4(MSH5):c.306G>A(p.Thr102Thr) 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 Benign (★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 8 hom. )

Consequence

MSH5
NM_172166.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.77

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 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 Benign. ClinVar VariationId is 718250.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.77 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (246/152232) while in subpopulation AFR AF = 0.00409 (170/41532). AF 95% confidence interval is 0.00359. There are 1 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,Unknown gene

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.306G>A	p.Thr102Thr	synonymous	Exon 4 of 25	NP_751898.1	O43196-1
MSH5	NM_172165.4		c.306G>A	p.Thr102Thr	synonymous	Exon 4 of 25	NP_751897.1	O43196-2
MSH5	NM_002441.5		c.306G>A	p.Thr102Thr	synonymous	Exon 4 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.306G>A	p.Thr102Thr	synonymous	Exon 4 of 25	ENSP00000364903.3	O43196-1
MSH5	ENST00000375703.7	TSL:1	c.306G>A	p.Thr102Thr	synonymous	Exon 4 of 25	ENSP00000364855.3	O43196-2
MSH5	ENST00000375755.8	TSL:1	c.306G>A	p.Thr102Thr	synonymous	Exon 4 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes

AF:

0.00155

AC:

236

AN:

152114

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.000835

AC:

206

AN:

246592

AF XY:

0.000774

show subpopulations

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 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.:

Cov.:

AF XY:

0.000661

AC XY:

480

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.00511

AC:

171

AN:

33480

American (AMR)

AF:

0.00107

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00126

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52312

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000525

AC:

584

AN:

1112004

Other (OTH)

AF:

0.00177

AC:

107

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00162

AC:

246

AN:

152232

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

119

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00409

AC:

170

AN:

41532

American (AMR)

AF:

0.00131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68012

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000843

Hom.:

Bravo

AF:

0.00182

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

MSH5-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

2.1

(source)

DANN

Benign

0.82

PhyloP100

-2.8

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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