chr5-80678751-G-A

Variant names:

• chr5-80678751-G-A
• rs836808
• NM_002439.5:c.1174-176G>A

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.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
• 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, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.1174-176G>A		intron	N/A	NP_002430.3	P20585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.1174-176G>A		intron	N/A	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.1006-176G>A		intron	N/A	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.1174-176G>A		intron	N/A	ENSP00000499502.1	A0A590UJN8

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

African (AFR) AF: 0.274 AC: 11353 AN: 41436

American (AMR) AF: 0.222 AC: 3398 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 998 AN: 3470

East Asian (EAS) AF: 0.0238 AC: 123 AN: 5164

South Asian (SAS) AF: 0.276 AC: 1332 AN: 4822

European-Finnish (FIN) AF: 0.212 AC: 2241 AN: 10570

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17862 AN: 67976

Other (OTH) AF: 0.271 AC: 570 AN: 2104

Alfa AF: 0.264 Hom.: 2834

Bravo AF: 0.249

Asia WGS AF: 0.182 AC: 637 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.014
DANN	Benign	0.80
PhyloP100		-4.2
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: rs836808; hg19: chr5-79974570;