5-80781309-G-T

Variant names:

• chr5-80781309-G-T
• rs12513549
• NM_002439.5:c.2435+2473G>T

Variant summary

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

The NM_002439.5(MSH3):​c.2435+2473G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 151,906 control chromosomes in the GnomAD database, including 1,292 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 (1292 hom., cov: 31)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.208
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.2435+2473G>T		intron_variant	Intron 17 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.2435+2473G>T		intron_variant	Intron 17 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2267+2473G>T		intron_variant	Intron 17 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2240+2473G>T		intron_variant	Intron 15 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.2435+2473G>T		intron_variant	Intron 17 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19475 AN: 151788 Hom.: 1292 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.0972

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.128 AC: 19494 AN: 151906 Hom.: 1292 Cov.: 31 AF XY: 0.131 AC XY: 9727 AN XY: 74204

African (AFR) AF: 0.128 AC: 5298 AN: 41396

American (AMR) AF: 0.157 AC: 2398 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1425 AN: 5152

South Asian (SAS) AF: 0.0966 AC: 463 AN: 4792

European-Finnish (FIN) AF: 0.135 AC: 1422 AN: 10556

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7711 AN: 67974

Other (OTH) AF: 0.140 AC: 296 AN: 2114

Alfa AF: 0.121 Hom.: 224

Bravo AF: 0.132

Asia WGS AF: 0.199 AC: 693 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.45
PhyloP100		0.21
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: rs12513549; hg19: chr5-80077128;