chr1-239855007-T-G

Variant names:

• chr1-239855007-T-G
• rs528011
• NM_001375978.1:c.-20+27629T>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.-20+27629T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 152,000 control chromosomes in the GnomAD database, including 17,256 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 0.45 (17256 hom., cov: 33)
• Consequence: CHRM3 NM_001375978.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 7 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=-0.71).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 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.-20+27629T>G		intron	N/A	NP_001362907.1
	CHRM3	NM_000740.4		c.-20+27629T>G		intron	N/A	NP_000731.1
	CHRM3	NM_001347716.2		c.-20+27629T>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.-20+27629T>G		intron	N/A	ENSP00000502667.1
	CHRM3	ENST00000255380.8	TSL:1	c.-20+27629T>G		intron	N/A	ENSP00000255380.4
	CHRM3	ENST00000615928.5	TSL:5	c.-20+27629T>G		intron	N/A	ENSP00000482377.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68978 AN: 151882 Hom.: 17262 Cov.: 33

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.497

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.565

Gnomad SAS AF: 0.551

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.454

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

GnomAD4 genome AF: 0.454 AC: 68967 AN: 152000 Hom.: 17256 Cov.: 33 AF XY: 0.461 AC XY: 34279 AN XY: 74290

African (AFR) AF: 0.223 AC: 9235 AN: 41496

American (AMR) AF: 0.458 AC: 6982 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1962 AN: 3472

East Asian (EAS) AF: 0.565 AC: 2910 AN: 5154

South Asian (SAS) AF: 0.550 AC: 2652 AN: 4818

European-Finnish (FIN) AF: 0.649 AC: 6864 AN: 10578

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36814 AN: 67912

Other (OTH) AF: 0.448 AC: 945 AN: 2110

Alfa AF: 0.476 Hom.: 3345

Bravo AF: 0.429

Asia WGS AF: 0.505 AC: 1760 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.73
PhyloP100		2.1
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: rs528011; hg19: chr1-240018307;