Genetic Variant MSH3:c.1763+1841T>A (chr5-80746456-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002439.5(MSH3):c.1763+1841T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000589 in 339,472 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

MSH3
NM_002439.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

0 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:

ENSG00000248967 (HGNC:):

ENSG00000248967 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5 link	c.1763+1841T>A		intron_variant	Intron 12 of 23	ENST00000265081.7	NP_002430.3	P20585
LOC124901016		n.80746456T>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
MSH3	ENST00000265081.7 link	c.1763+1841T>A	intron_variant	Intron 12 of 23	1	NM_002439.5	ENSP00000265081.6	P20585
MSH3	ENST00000658259.1 link	c.1595+1841T>A	intron_variant	Intron 12 of 23			ENSP00000499617.1	A0A590UJW0
MSH3	ENST00000667069.1 link	c.1569-15090T>A	intron_variant	Intron 10 of 21			ENSP00000499502.1	A0A590UJN8
MSH3	ENST00000670357.1 link	n.1763+1841T>A	intron_variant	Intron 12 of 24			ENSP00000499791.1	A0A590UKC9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000589

AC:

AN:

339472

Hom.:

Cov.:

AF XY:

0.00000513

AC XY:

AN XY:

194876

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

9250

American (AMR)

AF:

0.00

AC:

AN:

31200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10876

East Asian (EAS)

AF:

0.00

AC:

AN:

11934

South Asian (SAS)

AF:

0.00

AC:

AN:

61816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1140

European-Non Finnish (NFE)

AF:

0.0000113

AC:

AN:

177224

Other (OTH)

AF:

0.00

AC:

AN:

15210

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.77

(source)

DANN

Benign

0.73

PhyloP100

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over