Genetic Variant MSH5:p.Gln716Gln (chr6-31761582-A-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_172166.4(MSH5):c.2148A>G(p.Gln716Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,613,718 control chromosomes in the GnomAD database, including 106,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.43 ( 15883 hom., cov: 33)

Exomes 𝑓: 0.34 ( 90547 hom. )

Consequence

MSH5
NM_172166.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.419

Publications

68 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 6-31761582-A-G is Benign according to our data. Variant chr6-31761582-A-G is described in ClinVar as Benign. ClinVar VariationId is 403112.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.419 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.641 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.2148A>G	p.Gln716Gln	synonymous	Exon 22 of 25	NP_751898.1	O43196-1
MSH5	NM_172165.4		c.2151A>G	p.Gln717Gln	synonymous	Exon 22 of 25	NP_751897.1	O43196-2
MSH5	NM_002441.5		c.2148A>G	p.Gln716Gln	synonymous	Exon 22 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.2148A>G	p.Gln716Gln	synonymous	Exon 22 of 25	ENSP00000364903.3	O43196-1
MSH5	ENST00000375703.7	TSL:1	c.2151A>G	p.Gln717Gln	synonymous	Exon 22 of 25	ENSP00000364855.3	O43196-2
MSH5	ENST00000375755.8	TSL:1	c.2148A>G	p.Gln716Gln	synonymous	Exon 22 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65835

AN:

151992

Hom.:

15848

Cov.:

show subpopulations

Gnomad AFR

AF:

0.648

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.411

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.495

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.427

GnomAD2 exomes

AF:

0.382

AC:

95769

AN:

250692

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.653

Gnomad AMR exome

AF:

0.422

Gnomad ASJ exome

AF:

0.306

Gnomad EAS exome

AF:

0.335

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.313

Gnomad OTH exome

AF:

0.361

GnomAD4 exome

AF:

0.344

AC:

503039

AN:

1461606

Hom.:

90547

Cov.:

AF XY:

0.346

AC XY:

251597

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.652

AC:

21832

AN:

33478

American (AMR)

AF:

0.418

AC:

18678

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

8238

AN:

26136

East Asian (EAS)

AF:

0.379

AC:

15062

AN:

39700

South Asian (SAS)

AF:

0.473

AC:

40762

AN:

86258

European-Finnish (FIN)

AF:

0.427

AC:

22692

AN:

53160

Middle Eastern (MID)

AF:

0.406

AC:

2336

AN:

5760

European-Non Finnish (NFE)

AF:

0.315

AC:

350795

AN:

1112002

Other (OTH)

AF:

0.375

AC:

22644

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

22282

44564

66845

89127

111409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11792

23584

35376

47168

58960

<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:

0.433

AC:

65921

AN:

152112

Hom.:

15883

Cov.:

AF XY:

0.437

AC XY:

32523

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.648

AC:

26890

AN:

41520

American (AMR)

AF:

0.412

AC:

6294

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1069

AN:

3468

East Asian (EAS)

AF:

0.347

AC:

1791

AN:

5166

South Asian (SAS)

AF:

0.495

AC:

2387

AN:

4824

European-Finnish (FIN)

AF:

0.446

AC:

4718

AN:

10582

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.317

AC:

21512

AN:

67950

Other (OTH)

AF:

0.430

AC:

907

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1838

3676

5513

7351

9189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.355

Hom.:

45971

Bravo

AF:

0.437

Asia WGS

AF:

0.515

AC:

1787

AN:

3478

EpiCase

AF:

0.299

EpiControl

AF:

0.303

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.4

(source)

DANN

Benign

0.77

PhyloP100

0.42

PromoterAI

-0.0024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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