1-239907644-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001375978.1(CHRM3):c.193G>A(p.Val65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,614,116 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 28 hom., cov: 32)

Exomes 𝑓: 0.016 ( 259 hom. )

Consequence

CHRM3
NM_001375978.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0850

Publications

13 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 links:

CHRM3-AS1 (HGNC:40150): (CHRM3 antisense RNA 1)

CHRM3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00343284).

BP6

Variant 1-239907644-G-A is Benign according to our data. Variant chr1-239907644-G-A is described in ClinVar as [Benign]. Clinvar id is 1576872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0135 (2055/152230) while in subpopulation SAS AF = 0.0375 (181/4824). AF 95% confidence interval is 0.0331. There are 28 homozygotes in GnomAd4. There are 1103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 28 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM3	NM_001375978.1 link	c.193G>A	p.Val65Ile	missense_variant	Exon 7 of 7	ENST00000676153.1	NP_001362907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM3	ENST00000676153.1 link	c.193G>A	p.Val65Ile	missense_variant	Exon 7 of 7		NM_001375978.1	ENSP00000502667.1		P20309

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2054

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.00521

Gnomad SAS

AF:

0.0373

Gnomad FIN

AF:

0.0455

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0174

AC:

4386

AN:

251400

AF XY:

0.0197

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00419

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00348

Gnomad FIN exome

AF:

0.0431

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0158

AC:

23099

AN:

1461886

Hom.:

259

Cov.:

AF XY:

0.0168

AC XY:

12200

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

33480

American (AMR)

AF:

0.00458

AC:

205

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00872

AC:

228

AN:

26136

East Asian (EAS)

AF:

0.00202

AC:

AN:

39698

South Asian (SAS)

AF:

0.0431

AC:

3716

AN:

86258

European-Finnish (FIN)

AF:

0.0421

AC:

2247

AN:

53420

Middle Eastern (MID)

AF:

0.0227

AC:

131

AN:

5768

European-Non Finnish (NFE)

AF:

0.0140

AC:

15541

AN:

1112006

Other (OTH)

AF:

0.0145

AC:

874

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1448

2896

4343

5791

7239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0135

AC:

2055

AN:

152230

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1103

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41544

American (AMR)

AF:

0.00576

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00837

AC:

AN:

3466

East Asian (EAS)

AF:

0.00522

AC:

AN:

5170

South Asian (SAS)

AF:

0.0375

AC:

181

AN:

4824

European-Finnish (FIN)

AF:

0.0455

AC:

482

AN:

10602

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0162

AC:

1100

AN:

68014

Other (OTH)

AF:

0.0147

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00861

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0127

AC:

109

ExAC

AF:

0.0180

AC:

2188

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0142

EpiControl

AF:

0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHRM3: PP2, BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.28

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.060

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.70

.;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;.

PhyloP100

-0.085

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.26

N;.;N

REVEL

Benign

0.086

Sift

Benign

0.49

T;.;T

Sift4G

Benign

0.084

T;T;D

Polyphen

0.0020

B;B;.

Vest4

0.021

MPC

0.39

ClinPred

0.0023

GERP RS

-11

Varity_R

0.025

gMVP

0.38

Mutation Taster

=98/2

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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1-239907644-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over