dbSNP rs2897298: MSH3:c.3000+3341G>A (chr5-80857657-G-A) – 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.3000+3341G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,120 control chromosomes in the GnomAD database, including 1,043 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 0.10 ( 1043 hom., cov: 32)

Consequence

MSH3
NM_002439.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.452

Publications

13 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=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.3000+3341G>A		intron_variant	Intron 21 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
MSH3	ENST00000265081.7 link	c.3000+3341G>A	intron_variant	Intron 21 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1 link	c.2832+3341G>A	intron_variant	Intron 21 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1 link	c.2805+3341G>A	intron_variant	Intron 19 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1 link	n.*324+3341G>A	intron_variant	Intron 22 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

15784

AN:

152002

Hom.:

1042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.0892

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.112

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

GnomAD4 genome

AF:

0.104

AC:

15787

AN:

152120

Hom.:

1043

Cov.:

AF XY:

0.106

AC XY:

7917

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0248

AC:

1032

AN:

41538

American (AMR)

AF:

0.145

AC:

2219

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

400

AN:

3430

East Asian (EAS)

AF:

0.242

AC:

1255

AN:

5178

South Asian (SAS)

AF:

0.0890

AC:

428

AN:

4808

European-Finnish (FIN)

AF:

0.148

AC:

1564

AN:

10564

Middle Eastern (MID)

AF:

0.112

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.126

AC:

8534

AN:

67984

Other (OTH)

AF:

0.116

AC:

245

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

723

1445

2168

2890

3613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<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:

0.104

Hom.:

432

Bravo

AF:

0.101

Asia WGS

AF:

0.173

AC:

600

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.0

(source)

DANN

Benign

0.84

PhyloP100

0.45

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