rs587776862

Variant names:

• chr1-239908624-GCCTGAGGAGGA-T
• rs587776862
• NM_001375978.1:c.1173_1184delGCCTGAGGAGGAinsT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_001375978.1(CHRM3):​c.1173_1184delGCCTGAGGAGGAinsT​(p.Pro392AlafsTer44) variant causes a frameshift, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRM3 NM_001375978.1 frameshift, synonymous
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.69
• Publications: 0 publications found

Genes affected

CHRM3 (HGNC:1952): (cholinergic receptor muscarinic 3) The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

CHRM3-AS1 (HGNC:40150): (CHRM3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.338 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 1-239908624-GCCTGAGGAGGA-T is Pathogenic according to our data. Variant chr1-239908624-GCCTGAGGAGGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29626.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375978.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM3	NM_001375978.1	MANE Select	c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 7 of 7	NP_001362907.1
	CHRM3	NM_000740.4		c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 5 of 5	NP_000731.1
	CHRM3	NM_001347716.2		c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 8 of 8	NP_001334645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM3	ENST00000676153.1	MANE Select	c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 7 of 7	ENSP00000502667.1
	CHRM3	ENST00000255380.8	TSL:1	c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 5 of 5	ENSP00000255380.4
	CHRM3	ENST00000615928.5	TSL:5	c.1173_1184delGCCTGAGGAGGAinsT	p.Pro392AlafsTer44	frameshift synonymous	Exon 6 of 6	ENSP00000482377.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Prune belly syndrome Pathogenic:1

Nov 11, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=14/186	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587776862; hg19: chr1-240071924;