Genetic Variant NM_002439.5:c.1341-4398T>C (chr5-80721055-T-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_002439.5(MSH3):c.1341-4398T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 151,994 control chromosomes in the GnomAD database, including 10,446 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 0.37 ( 10446 hom., cov: 32)

Consequence

MSH3
NM_002439.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.595

Publications

15 publications found

Variant links:

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 Gene-Disease associations (from GenCC):

familial adenomatous polyposis 4
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
MSH3-related attenuated familial adenomatous polyposis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Lynch syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MSH3 links:

Genome browser will be placed here

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=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.1341-4398T>C		intron_variant	Intron 8 of 23	ENST00000265081.7	NP_002430.3	P20585

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 link	c.1341-4398T>C	intron_variant	Intron 8 of 23	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 link	c.1173-4398T>C	intron_variant	Intron 8 of 23			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 link	c.1341-4398T>C	intron_variant	Intron 8 of 21			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 link	n.1341-4398T>C	intron_variant	Intron 8 of 24			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

AF:

0.367

AC:

55699

AN:

151876

Hom.:

10436

Cov.:

show subpopulations

Gnomad AFR

AF:

0.447

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.428

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.356

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.275

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.317

Gnomad OTH

AF:

0.373

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.367

AC:

55735

AN:

151994

Hom.:

10446

Cov.:

AF XY:

0.366

AC XY:

27173

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.446

AC:

18493

AN:

41424

American (AMR)

AF:

0.428

AC:

6530

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1491

AN:

3468

East Asian (EAS)

AF:

0.356

AC:

1837

AN:

5166

South Asian (SAS)

AF:

0.356

AC:

1715

AN:

4816

European-Finnish (FIN)

AF:

0.275

AC:

2908

AN:

10562

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.317

AC:

21553

AN:

67974

Other (OTH)

AF:

0.373

AC:

787

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1801

3603

5404

7206

9007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.338

Hom.:

14863

Bravo

AF:

0.384

Asia WGS

AF:

0.357

AC:

1242

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

6.6

(source)

DANN

Benign

0.71

PhyloP100

-0.59

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over