rs2067481

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr1-239907644-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 28 AR 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

GnomAD3 exomes

AF:

0.0174

AC:

4386

AN:

251400

Hom.:

AF XY:

0.0197

AC XY:

2683

AN XY:

135870

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 SAS exome

AF:

0.0414

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

Gnomad4 AFR exome

AF:

0.00230

Gnomad4 AMR exome

AF:

0.00458

Gnomad4 ASJ exome

AF:

0.00872

Gnomad4 EAS exome

AF:

0.00202

Gnomad4 SAS exome

AF:

0.0431

Gnomad4 FIN exome

AF:

0.0421

Gnomad4 NFE exome

AF:

0.0140

Gnomad4 OTH exome

AF:

0.0145

GnomAD4 genome

AF:

0.0135

AC:

2055

AN:

152230

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1103

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.00576

Gnomad4 ASJ

AF:

0.00837

Gnomad4 EAS

AF:

0.00522

Gnomad4 SAS

AF:

0.0375

Gnomad4 FIN

AF:

0.0455

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0137

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHRM3: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over