NM_002439.5:c.238-196A>G

Variant names:

• chr5-80656215-A-G
• rs380691
• NM_002439.5:c.238-196A>G

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.238-196A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 152,048 control chromosomes in the GnomAD database, including 7,303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7303 hom., cov: 32)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120
• Publications: 29 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=-0.87).
• BP6: Variant 5-80656215-A-G is Benign according to our data. Variant chr5-80656215-A-G is described in ClinVar as Benign. ClinVar VariationId is 1281689.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.238-196A>G		intron_variant	Intron 1 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.238-196A>G		intron_variant	Intron 1 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.70-196A>G		intron_variant	Intron 1 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.238-196A>G		intron_variant	Intron 1 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.238-196A>G		intron_variant	Intron 1 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44167 AN: 151930 Hom.: 7304 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.288

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

GnomAD4 genome AF: 0.290 AC: 44169 AN: 152048 Hom.: 7303 Cov.: 32 AF XY: 0.293 AC XY: 21772 AN XY: 74330

African (AFR) AF: 0.140 AC: 5794 AN: 41500

American (AMR) AF: 0.377 AC: 5760 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1255 AN: 3464

East Asian (EAS) AF: 0.599 AC: 3091 AN: 5156

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4818

European-Finnish (FIN) AF: 0.335 AC: 3534 AN: 10564

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22577 AN: 67956

Other (OTH) AF: 0.288 AC: 609 AN: 2114

Alfa AF: 0.322 Hom.: 35392

Bravo AF: 0.295

Asia WGS AF: 0.360 AC: 1250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 13, 2021

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	-0.87
CADD	Benign	7.5
DANN	Benign	0.55
PhyloP100		-0.012
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: rs380691; hg19: chr5-79952034;