NM_002439.5:c.2813+6530G>A

Variant names:

• chr5-80820271-G-A
• rs32989
• NM_002439.5:c.2813+6530G>A

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+6530G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 152,080 control chromosomes in the GnomAD database, including 37,901 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 0.71 (37901 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• Publications: 5 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=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.2813+6530G>A		intron	N/A	NP_002430.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.2813+6530G>A		intron	N/A	ENSP00000265081.6
	MSH3	ENST00000658259.1		c.2645+6530G>A		intron	N/A	ENSP00000499617.1
	MSH3	ENST00000667069.1		c.2618+6530G>A		intron	N/A	ENSP00000499502.1

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107287 AN: 151962 Hom.: 37876 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.795

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.672

Gnomad NFE AF: 0.717

Gnomad OTH AF: 0.701

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

GnomAD4 genome AF: 0.706 AC: 107365 AN: 152080 Hom.: 37901 Cov.: 32 AF XY: 0.707 AC XY: 52577 AN XY: 74368

African (AFR) AF: 0.667 AC: 27698 AN: 41498

American (AMR) AF: 0.703 AC: 10725 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.685 AC: 2376 AN: 3470

East Asian (EAS) AF: 0.756 AC: 3904 AN: 5162

South Asian (SAS) AF: 0.797 AC: 3836 AN: 4816

European-Finnish (FIN) AF: 0.729 AC: 7706 AN: 10574

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.717 AC: 48722 AN: 67982

Other (OTH) AF: 0.700 AC: 1476 AN: 2110

Alfa AF: 0.706 Hom.: 63556

Bravo AF: 0.700

Asia WGS AF: 0.737 AC: 2559 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.9
DANN	Benign	0.73
PhyloP100		0.35
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: rs32989; hg19: chr5-80116090;