5-80830334-A-G

Variant names:

• chr5-80830334-A-G
• rs249633
• NM_002439.5:c.2813+16593A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002439.5(MSH3):​c.2813+16593A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,054 control chromosomes in the GnomAD database, including 3,441 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 0.20 (3441 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.2813+16593A>G		intron_variant	Intron 20 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.2813+16593A>G		intron_variant	Intron 20 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2645+16593A>G		intron_variant	Intron 20 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2618+16593A>G		intron_variant	Intron 18 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.2813+16593A>G		intron_variant	Intron 20 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30705 AN: 151936 Hom.: 3440 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0948

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.200

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

GnomAD4 genome AF: 0.202 AC: 30714 AN: 152054 Hom.: 3441 Cov.: 32 AF XY: 0.204 AC XY: 15137 AN XY: 74342

African (AFR) AF: 0.122 AC: 5072 AN: 41510

American (AMR) AF: 0.166 AC: 2529 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3470

East Asian (EAS) AF: 0.0950 AC: 492 AN: 5178

South Asian (SAS) AF: 0.358 AC: 1720 AN: 4800

European-Finnish (FIN) AF: 0.258 AC: 2718 AN: 10546

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16691 AN: 67958

Other (OTH) AF: 0.200 AC: 422 AN: 2108

Alfa AF: 0.238 Hom.: 2296

Bravo AF: 0.184

Asia WGS AF: 0.225 AC: 784 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.22
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs249633; hg19: chr5-80126153;