rs1677658

Positions:

• chr5-80655040-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.237+76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 867,144 control chromosomes in the GnomAD database, including 10,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1211 hom., cov: 30)
  • Exomes 𝑓: 0.15 (9518 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0510

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=-0.76).
• BP6: Variant 5-80655040-G-T is Benign according to our data. Variant chr5-80655040-G-T is described in ClinVar as [Benign]. Clinvar id is 1261132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.237+76G>T		intron_variant		ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.237+76G>T		intron_variant		1	NM_002439.5	P2
MSH3	ENST00000667069.1	c.237+76G>T		intron_variant
MSH3	ENST00000670357.1	c.237+76G>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17873 AN: 151624 Hom.: 1211 Cov.: 30

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.000976

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.146 AC: 104802 AN: 715412 Hom.: 9518 Cov.: 10 AF XY: 0.149 AC XY: 53990 AN XY: 362548

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.000492

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.118 AC: 17865 AN: 151732 Hom.: 1211 Cov.: 30 AF XY: 0.116 AC XY: 8584 AN XY: 74154

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.000979

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.139

Alfa AF: 0.129 Hom.: 156

Bravo AF: 0.116

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 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.2
DANN	Benign	0.94

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: rs1677658; hg19: chr5-79950859;