rs6688537

Variant names:

• chr1-239687288-C-A
• rs6688537
• NM_001375978.1:c.-147+9000C>A

Variant summary

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

The NM_001375978.1(CHRM3):​c.-147+9000C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 151,866 control chromosomes in the GnomAD database, including 23,364 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 0.55 (23364 hom., cov: 32)
• Consequence: CHRM3 NM_001375978.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.189
• Publications: 8 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 (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM3	NM_001375978.1	c.-147+9000C>A		intron_variant	Intron 5 of 6	ENST00000676153.1	NP_001362907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM3	ENST00000676153.1	c.-147+9000C>A		intron_variant	Intron 5 of 6		NM_001375978.1	ENSP00000502667.1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82878 AN: 151748 Hom.: 23319 Cov.: 32

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.546

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.509

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.546 AC: 82983 AN: 151866 Hom.: 23364 Cov.: 32 AF XY: 0.544 AC XY: 40376 AN XY: 74200

African (AFR) AF: 0.661 AC: 27402 AN: 41430

American (AMR) AF: 0.578 AC: 8819 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 1893 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2424 AN: 5150

South Asian (SAS) AF: 0.509 AC: 2453 AN: 4820

European-Finnish (FIN) AF: 0.420 AC: 4415 AN: 10522

Middle Eastern (MID) AF: 0.579 AC: 169 AN: 292

European-Non Finnish (NFE) AF: 0.497 AC: 33753 AN: 67894

Other (OTH) AF: 0.546 AC: 1154 AN: 2112

Alfa AF: 0.520 Hom.: 2628

Bravo AF: 0.563

Asia WGS AF: 0.540 AC: 1877 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.47
DANN	Benign	0.24
PhyloP100		-0.19
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: rs6688537; hg19: chr1-239850588; COSMIC: COSV55101793;