rs1650694

Variant names:

• chr5-80656607-G-A
• rs1650694
• NM_002439.5:c.358+76G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-80656607-G-A
• chr5-80656607-G-C
• chr5-80656607-G-T

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.358+76G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,588,906 control chromosomes in the GnomAD database, including 7,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1033 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6252 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.76
• 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=-0.9).
• BP6: Variant 5-80656607-G-A is Benign according to our data. Variant chr5-80656607-G-A is described in ClinVar as Benign. ClinVar VariationId is 1246069.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.358+76G>A		intron_variant	Intron 2 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.358+76G>A		intron_variant	Intron 2 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.190+76G>A		intron_variant	Intron 2 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.358+76G>A		intron_variant	Intron 2 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.358+76G>A		intron_variant	Intron 2 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16735 AN: 151980 Hom.: 1033 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.243

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.0482

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.107

GnomAD4 exome AF: 0.0901 AC: 129429 AN: 1436808 Hom.: 6252 AF XY: 0.0891 AC XY: 63827 AN XY: 716082

African (AFR) AF: 0.173 AC: 5680 AN: 32792

American (AMR) AF: 0.0802 AC: 3528 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.0545 AC: 1407 AN: 25838

East Asian (EAS) AF: 0.0369 AC: 1453 AN: 39416

South Asian (SAS) AF: 0.0719 AC: 6116 AN: 85040

European-Finnish (FIN) AF: 0.100 AC: 5267 AN: 52448

Middle Eastern (MID) AF: 0.0603 AC: 343 AN: 5686

European-Non Finnish (NFE) AF: 0.0921 AC: 100587 AN: 1092212

Other (OTH) AF: 0.0850 AC: 5048 AN: 59404

GnomAD4 genome AF: 0.110 AC: 16748 AN: 152098 Hom.: 1033 Cov.: 32 AF XY: 0.109 AC XY: 8110 AN XY: 74354

African (AFR) AF: 0.169 AC: 7004 AN: 41476

American (AMR) AF: 0.0887 AC: 1356 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0482 AC: 167 AN: 3468

East Asian (EAS) AF: 0.0172 AC: 89 AN: 5184

South Asian (SAS) AF: 0.0661 AC: 319 AN: 4824

European-Finnish (FIN) AF: 0.102 AC: 1075 AN: 10570

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0923 AC: 6274 AN: 67982

Other (OTH) AF: 0.106 AC: 223 AN: 2100

Alfa AF: 0.0539 Hom.: 81

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 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	-0.90
CADD	Benign	1.2
DANN	Benign	0.91
PhyloP100		-1.8
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: rs1650694; hg19: chr5-79952426;