Genetic Variant NM_002439.5:c.237+713G>T (chr5-80655677-G-T) – 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.237+713G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 180,072 control chromosomes in the GnomAD database, including 9,158 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 0.27 ( 7004 hom., cov: 32)

Exomes 𝑓: 0.37 ( 2154 hom. )

Consequence

MSH3
NM_002439.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.168

Publications

20 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=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.237+713G>T		intron_variant	Intron 1 of 23	ENST00000265081.7	NP_002430.3	P20585

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 link	c.237+713G>T	intron_variant	Intron 1 of 23	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 link	c.69+415G>T	intron_variant	Intron 1 of 23			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 link	c.237+713G>T	intron_variant	Intron 1 of 21			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 link	n.237+713G>T	intron_variant	Intron 1 of 24			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

41469

AN:

152020

Hom.:

7006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0774

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.362

Gnomad EAS

AF:

0.600

Gnomad SAS

AF:

0.249

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.276

GnomAD4 exome

AF:

0.374

AC:

10459

AN:

27934

Hom.:

2154

AF XY:

0.371

AC XY:

4745

AN XY:

12802

show subpopulations

African (AFR)

AF:

0.0825

AC:

AN:

946

American (AMR)

AF:

0.370

AC:

234

AN:

632

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

663

AN:

1814

East Asian (EAS)

AF:

0.607

AC:

3449

AN:

5686

South Asian (SAS)

AF:

0.224

AC:

AN:

232

European-Finnish (FIN)

AF:

0.154

AC:

AN:

Middle Eastern (MID)

AF:

0.180

AC:

AN:

178

European-Non Finnish (NFE)

AF:

0.323

AC:

5218

AN:

16152

Other (OTH)

AF:

0.321

AC:

729

AN:

2268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

274

548

823

1097

1371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.273

AC:

41465

AN:

152138

Hom.:

7004

Cov.:

AF XY:

0.276

AC XY:

20505

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0771

AC:

3205

AN:

41544

American (AMR)

AF:

0.371

AC:

5664

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.362

AC:

1255

AN:

3468

East Asian (EAS)

AF:

0.600

AC:

3090

AN:

5152

South Asian (SAS)

AF:

0.249

AC:

1201

AN:

4820

European-Finnish (FIN)

AF:

0.336

AC:

3552

AN:

10584

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22567

AN:

67972

Other (OTH)

AF:

0.276

AC:

583

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1400

2800

4200

5600

7000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.311

Hom.:

12012

Bravo

AF:

0.275

Asia WGS

AF:

0.356

AC:

1235

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.1

(source)

DANN

Benign

0.67

PhyloP100

-0.17

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over