chr1-239806797-A-G

Variant names:

• chr1-239806797-A-G
• rs12059546
• NM_001375978.1:c.-146-20455A>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.-146-20455A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,174 control chromosomes in the GnomAD database, including 8,034 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 0.29 (8034 hom., cov: 33)
• Consequence: CHRM3 NM_001375978.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 16 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 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.-146-20455A>G		intron	N/A	NP_001362907.1
	CHRM3	NM_000740.4		c.-146-20455A>G		intron	N/A	NP_000731.1
	CHRM3	NM_001347716.2		c.-375-20056A>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.-146-20455A>G		intron	N/A	ENSP00000502667.1
	CHRM3	ENST00000255380.8	TSL:1	c.-146-20455A>G		intron	N/A	ENSP00000255380.4
	CHRM3	ENST00000615928.5	TSL:5	c.-146-20455A>G		intron	N/A	ENSP00000482377.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44603 AN: 152056 Hom.: 8022 Cov.: 33

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.293 AC: 44639 AN: 152174 Hom.: 8034 Cov.: 33 AF XY: 0.289 AC XY: 21498 AN XY: 74394

African (AFR) AF: 0.511 AC: 21188 AN: 41494

American (AMR) AF: 0.255 AC: 3897 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3468

East Asian (EAS) AF: 0.311 AC: 1609 AN: 5176

South Asian (SAS) AF: 0.197 AC: 951 AN: 4826

European-Finnish (FIN) AF: 0.183 AC: 1938 AN: 10588

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13536 AN: 68020

Other (OTH) AF: 0.269 AC: 567 AN: 2110

Alfa AF: 0.225 Hom.: 18920

Bravo AF: 0.307

Asia WGS AF: 0.298 AC: 1038 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.2
DANN	Benign	0.68
PhyloP100		-0.049
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12059546; hg19: chr1-239970097;