1-239644620-A-G

Variant names:

• chr1-239644620-A-G
• rs1867263
• NM_001375978.1:c.-250+12334A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001375978.1(CHRM3):​c.-250+12334A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 151,984 control chromosomes in the GnomAD database, including 33,415 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (33415 hom., cov: 31)
• Consequence: CHRM3 NM_001375978.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 4 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 Gene-Disease associations (from GenCC):

• prune belly syndrome

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

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.-250+12334A>G		intron	N/A	NP_001362907.1
	CHRM3	NM_000740.4		c.-250+12334A>G		intron	N/A	NP_000731.1
	CHRM3	NM_001347716.2		c.-479+12334A>G		intron	N/A	NP_001334645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM3	ENST00000676153.1	MANE Select	c.-250+12334A>G		intron	N/A	ENSP00000502667.1
	CHRM3	ENST00000255380.8	TSL:1	c.-250+12334A>G		intron	N/A	ENSP00000255380.4
	CHRM3	ENST00000615928.5	TSL:5	c.-250+12334A>G		intron	N/A	ENSP00000482377.1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100135 AN: 151864 Hom.: 33376 Cov.: 31

Gnomad AFR AF: 0.682

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.642

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

GnomAD4 genome AF: 0.659 AC: 100230 AN: 151984 Hom.: 33415 Cov.: 31 AF XY: 0.666 AC XY: 49426 AN XY: 74260

African (AFR) AF: 0.682 AC: 28279 AN: 41446

American (AMR) AF: 0.725 AC: 11080 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2008 AN: 3470

East Asian (EAS) AF: 0.838 AC: 4305 AN: 5140

South Asian (SAS) AF: 0.660 AC: 3173 AN: 4808

European-Finnish (FIN) AF: 0.689 AC: 7282 AN: 10568

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42081 AN: 67960

Other (OTH) AF: 0.644 AC: 1361 AN: 2112

Alfa AF: 0.633 Hom.: 138414

Bravo AF: 0.666

Asia WGS AF: 0.719 AC: 2496 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.14
DANN	Benign	0.65
PhyloP100		-1.0
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: rs1867263; hg19: chr1-239807920;