Variant 11-46385705-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000741.5(CHRM4):c.853C>T(p.Arg285Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000025 in 1,560,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CHRM4
NM_000741.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

Variant links:

Genes affected

CHRM4 (HGNC:1953): (cholinergic receptor muscarinic 4) 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 clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition. [provided by RefSeq, Jul 2008]

CHRM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27987844).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM4	NM_000741.5 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	2/2	ENST00000682254.1	NP_000732.2	P08173
CHRM4	NM_001366692.2 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	2/2		NP_001353621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRM4	ENST00000682254.1 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	2/2		NM_000741.5	ENSP00000507561.1		P08173
CHRM4	ENST00000433765.3 linkuse as main transcript	c.853C>T	p.Arg285Cys	missense_variant	1/1	6		ENSP00000409378.2		P08173

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000544

AC:

AN:

202332

Hom.:

AF XY:

0.0000549

AC XY:

AN XY:

109364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000710

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000184

Gnomad SAS exome

AF:

0.000183

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.000212

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1408370

Hom.:

Cov.:

AF XY:

0.0000230

AC XY:

AN XY:

695870

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000531

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000763

Gnomad4 SAS exome

AF:

0.0000385

Gnomad4 FIN exome

AF:

0.0000409

Gnomad4 NFE exome

AF:

0.0000221

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000500

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

The c.853C>T (p.R285C) alteration is located in exon 1 (coding exon 1) of the CHRM4 gene. This alteration results from a C to T substitution at nucleotide position 853, causing the arginine (R) at amino acid position 285 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.23

Eigen

Benign

0.076

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.090

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.3

REVEL

Benign

0.27

Sift

Benign

0.10

Sift4G

Benign

0.072

Polyphen

0.99

Vest4

0.23

MutPred

0.52

Gain of catalytic residue at V287 (P = 0.0371);

MVP

0.87

MPC

1.2

ClinPred

0.096

GERP RS

4.1

Varity_R

0.079

gMVP

0.26

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