rs245346

Positions:

• chr5-80860240-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002439.5(MSH3):​c.3001-4573A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 152,012 control chromosomes in the GnomAD database, including 15,890 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 0.44 (15890 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.3001-4573A>G		intron_variant		ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.3001-4573A>G		intron_variant		1	NM_002439.5	P2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66637 AN: 151894 Hom.: 15888 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.526

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.541

Gnomad OTH AF: 0.452

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

GnomAD4 genome AF: 0.438 AC: 66651 AN: 152012 Hom.: 15890 Cov.: 32 AF XY: 0.440 AC XY: 32661 AN XY: 74274

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.527

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.541

Gnomad4 OTH AF: 0.450

Alfa AF: 0.502 Hom.: 7767

Bravo AF: 0.412

Asia WGS AF: 0.421 AC: 1461 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.030
DANN	Benign	0.39

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

LitVar

Other links and lift over

dbSNP: rs245346; hg19: chr5-80156059; COSMIC: COSV54148069; COSMIC: COSV54148069;