rs836808

chr5-80678751-G-A

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.1174-176G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,022 control chromosomes in the GnomAD database, including 4,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.25 (4901 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.23

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=-1.01).
• BP6: Variant 5-80678751-G-A is Benign according to our data. Variant chr5-80678751-G-A is described in ClinVar as [Benign]. Clinvar id is 1289501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.27 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.1174-176G>A		intron_variant		ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.1174-176G>A		intron_variant		1	NM_002439.5	P2
MSH3	ENST00000658259.1	c.1006-176G>A		intron_variant				A2
MSH3	ENST00000667069.1	c.1174-176G>A		intron_variant
MSH3	ENST00000670357.1	c.1174-176G>A		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38196 AN: 151904 Hom.: 4899 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.0236

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.251 AC: 38204 AN: 152022 Hom.: 4901 Cov.: 32 AF XY: 0.247 AC XY: 18373 AN XY: 74316

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.0238

Gnomad4 SAS AF: 0.276

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.271

Alfa AF: 0.264 Hom.: 2535

Bravo AF: 0.249

Asia WGS AF: 0.182 AC: 637 AN: 3478

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

May 13, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.014
Dann	Benign	0.80

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: rs836808; hg19: chr5-79974570;