rs4703819

Variant names:

• chr5-80869595-C-G
• rs4703819
• NM_002439.5:c.3131-3521C>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.3131-3521C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 151,778 control chromosomes in the GnomAD database, including 1,561 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 0.13 (1561 hom., cov: 30)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 3 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.3131-3521C>G		intron_variant	Intron 22 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.3131-3521C>G		intron_variant	Intron 22 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2963-3521C>G		intron_variant	Intron 22 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2936-3521C>G		intron_variant	Intron 20 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.*455-3521C>G		intron_variant	Intron 23 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19121 AN: 151664 Hom.: 1560 Cov.: 30

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.0707

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0766

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.126 AC: 19138 AN: 151778 Hom.: 1561 Cov.: 30 AF XY: 0.128 AC XY: 9516 AN XY: 74154

African (AFR) AF: 0.161 AC: 6667 AN: 41366

American (AMR) AF: 0.214 AC: 3253 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 528 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1817 AN: 5158

South Asian (SAS) AF: 0.116 AC: 558 AN: 4806

European-Finnish (FIN) AF: 0.0707 AC: 742 AN: 10494

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0766 AC: 5207 AN: 67988

Other (OTH) AF: 0.121 AC: 254 AN: 2102

Alfa AF: 0.110 Hom.: 146

Bravo AF: 0.147

Asia WGS AF: 0.196 AC: 682 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.3
DANN	Benign	0.61
PhyloP100		0.13
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: rs4703819; hg19: chr5-80165414;