rs1650694

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	UniProt
MSH3	NM_002439.5	c.358+76G>A		intron_variant		ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.358+76G>A		intron_variant		1	NM_002439.5	P2
MSH3	ENST00000658259.1	c.190+76G>A		intron_variant				A2
MSH3	ENST00000667069.1	c.358+76G>A		intron_variant
MSH3	ENST00000670357.1	c.358+76G>A		intron_variant, NMD_transcript_variant

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

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.0802

Gnomad4 ASJ exome AF: 0.0545

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.0719

Gnomad4 FIN exome AF: 0.100

Gnomad4 NFE exome AF: 0.0921

Gnomad4 OTH exome AF: 0.0850

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

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0887

Gnomad4 ASJ AF: 0.0482

Gnomad4 EAS AF: 0.0172

Gnomad4 SAS AF: 0.0661

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0923

Gnomad4 OTH AF: 0.106

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.91

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: rs1650694; hg19: chr5-79952426;