dbSNP rs11964779: MSH5:c.416-57A>C (chr6-31743847-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_172166.4(MSH5):c.416-57A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,591,922 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.027 ( 161 hom., cov: 31)

Exomes 𝑓: 0.0046 ( 177 hom. )

Consequence

MSH5
NM_172166.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.668

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0831 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	Effect	Exon Rank	Protein	UniProt
MSH5	NM_172166.4	MANE Select	c.416-57A>C	intron	N/A	NP_751898.1	O43196-1
MSH5	NM_172165.4		c.416-57A>C	intron	N/A	NP_751897.1	O43196-2
MSH5	NM_002441.5		c.416-57A>C	intron	N/A	NP_002432.1	A0A024RCM1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MSH5	ENST00000375750.9	TSL:1 MANE Select	c.416-57A>C	intron	N/A	ENSP00000364903.3	O43196-1
MSH5	ENST00000375703.7	TSL:1	c.416-57A>C	intron	N/A	ENSP00000364855.3	O43196-2
MSH5	ENST00000375755.8	TSL:1	c.416-57A>C	intron	N/A	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4123

AN:

152090

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0857

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.00540

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.0263

GnomAD4 exome

AF:

0.00463

AC:

6667

AN:

1439714

Hom.:

177

AF XY:

0.00422

AC XY:

3014

AN XY:

715046

show subpopulations

African (AFR)

AF:

0.0886

AC:

2882

AN:

32546

American (AMR)

AF:

0.0233

AC:

962

AN:

41352

Ashkenazi Jewish (ASJ)

AF:

0.000887

AC:

AN:

24794

East Asian (EAS)

AF:

0.00692

AC:

273

AN:

39466

South Asian (SAS)

AF:

0.00173

AC:

144

AN:

83380

European-Finnish (FIN)

AF:

0.000252

AC:

AN:

51656

Middle Eastern (MID)

AF:

0.0145

AC:

AN:

5654

European-Non Finnish (NFE)

AF:

0.00155

AC:

1712

AN:

1101412

Other (OTH)

AF:

0.00970

AC:

577

AN:

59454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

346

692

1038

1384

1730

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<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:

0.0271

AC:

4124

AN:

152208

Hom.:

161

Cov.:

AF XY:

0.0267

AC XY:

1987

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0855

AC:

3547

AN:

41498

American (AMR)

AF:

0.0195

AC:

298

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00347

AC:

AN:

5182

South Asian (SAS)

AF:

0.00540

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

68018

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

191

381

572

762

953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0136

Hom.:

185

Bravo

AF:

0.0313

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.5

(source)

DANN

Benign

0.87

PhyloP100

-0.67

PromoterAI

0.028

Neutral

(source)

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

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