rs33010

Variant names:

• chr5-80787812-G-A
• rs33010
• NM_002439.5:c.2543+140G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002439.5(MSH3):​c.2543+140G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.85 in 660,196 control chromosomes in the GnomAD database, including 239,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.85 (54469 hom., cov: 33)
  • Exomes 𝑓: 0.85 (184677 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.441
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-80787812-G-A is Benign according to our data. Variant chr5-80787812-G-A is described in ClinVar as Benign. ClinVar VariationId is 1251794.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.2543+140G>A		intron_variant	Intron 18 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.2543+140G>A		intron_variant	Intron 18 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2375+140G>A		intron_variant	Intron 18 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2348+140G>A		intron_variant	Intron 16 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.2543+140G>A		intron_variant	Intron 18 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128652 AN: 152142 Hom.: 54420 Cov.: 33

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.797

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.868

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.836

GnomAD4 exome AF: 0.851 AC: 432374 AN: 507936 Hom.: 184677 AF XY: 0.851 AC XY: 233362 AN XY: 274088

African (AFR) AF: 0.838 AC: 11618 AN: 13868

American (AMR) AF: 0.892 AC: 26740 AN: 29964

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 14438 AN: 17602

East Asian (EAS) AF: 1.00 AC: 29494 AN: 29508

South Asian (SAS) AF: 0.871 AC: 49359 AN: 56700

European-Finnish (FIN) AF: 0.864 AC: 29906 AN: 34596

Middle Eastern (MID) AF: 0.772 AC: 1658 AN: 2148

European-Non Finnish (NFE) AF: 0.831 AC: 245994 AN: 296050

Other (OTH) AF: 0.842 AC: 23167 AN: 27500

GnomAD4 genome AF: 0.846 AC: 128758 AN: 152260 Hom.: 54469 Cov.: 33 AF XY: 0.849 AC XY: 63192 AN XY: 74436

African (AFR) AF: 0.839 AC: 34853 AN: 41552

American (AMR) AF: 0.859 AC: 13137 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 2766 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5186 AN: 5192

South Asian (SAS) AF: 0.867 AC: 4183 AN: 4824

European-Finnish (FIN) AF: 0.868 AC: 9194 AN: 10588

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.833 AC: 56671 AN: 68016

Other (OTH) AF: 0.838 AC: 1770 AN: 2112

Alfa AF: 0.834 Hom.: 26799

Bravo AF: 0.845

Asia WGS AF: 0.920 AC: 3199 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.2
DANN	Benign	0.52
PhyloP100		0.44
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: rs33010; hg19: chr5-80083631;