Genetic Variant CHRM3:c.-146-14250A>G (chr1-239813002-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001375978.1(CHRM3):c.-146-14250A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 152,084 control chromosomes in the GnomAD database, including 23,170 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 0.54 ( 23170 hom., cov: 34)

Consequence

CHRM3
NM_001375978.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.32

Publications

1 publications found

Variant links:

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

CHRM3 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.696 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRM3	NM_001375978.1	MANE Select	c.-146-14250A>G	intron	N/A	NP_001362907.1	P20309
CHRM3	NM_000740.4		c.-146-14250A>G	intron	N/A	NP_000731.1	P20309
CHRM3	NM_001347716.2		c.-375-13851A>G	intron	N/A	NP_001334645.1	P20309

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRM3	ENST00000676153.1	MANE Select	c.-146-14250A>G	intron	N/A	ENSP00000502667.1	P20309
CHRM3	ENST00000255380.8	TSL:1	c.-146-14250A>G	intron	N/A	ENSP00000255380.4	P20309
CHRM3	ENST00000615928.5	TSL:5	c.-146-14250A>G	intron	N/A	ENSP00000482377.1	P20309

Frequencies

GnomAD3 genomes

AF:

0.540

AC:

82123

AN:

151966

Hom.:

23136

Cov.:

show subpopulations

Gnomad AFR

AF:

0.703

Gnomad AMI

AF:

0.463

Gnomad AMR

AF:

0.461

Gnomad ASJ

AF:

0.514

Gnomad EAS

AF:

0.631

Gnomad SAS

AF:

0.442

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.484

Gnomad OTH

AF:

0.541

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

GnomAD4 genome

AF:

0.541

AC:

82206

AN:

152084

Hom.:

23170

Cov.:

AF XY:

0.535

AC XY:

39783

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.703

AC:

29169

AN:

41492

American (AMR)

AF:

0.460

AC:

7030

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.514

AC:

1783

AN:

3468

East Asian (EAS)

AF:

0.631

AC:

3250

AN:

5152

South Asian (SAS)

AF:

0.442

AC:

2127

AN:

4810

European-Finnish (FIN)

AF:

0.398

AC:

4205

AN:

10578

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.484

AC:

32904

AN:

67978

Other (OTH)

AF:

0.545

AC:

1151

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

1890

3779

5669

7558

9448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.273

Hom.:

442

Bravo

AF:

0.554

Asia WGS

AF:

0.598

AC:

2078

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.64

(source)

DANN

Benign

0.21

PhyloP100

-3.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over