Variant 11-46385771-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000741.5(CHRM4):c.787G>A(p.Ala263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,594,994 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 2 hom. )

Consequence

CHRM4
NM_000741.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.818

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05109483).

BS2

High AC in GnomAdExome4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRM4	NM_000741.5 linkuse as main transcript	c.787G>A	p.Ala263Thr	missense_variant	2/2	ENST00000682254.1	NP_000732.2	P08173
CHRM4	NM_001366692.2 linkuse as main transcript	c.787G>A	p.Ala263Thr	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.787G>A	p.Ala263Thr	missense_variant	2/2		NM_000741.5	ENSP00000507561.1		P08173
CHRM4	ENST00000433765.3 linkuse as main transcript	c.787G>A	p.Ala263Thr	missense_variant	1/1	6		ENSP00000409378.2		P08173

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000366

AC:

AN:

218762

Hom.:

AF XY:

0.0000167

AC XY:

AN XY:

119826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000625

Gnomad OTH exome

AF:

0.000368

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1442816

Hom.:

Cov.:

AF XY:

0.0000559

AC XY:

AN XY:

716072

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000717

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000937

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000418

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

May 01, 2024

The c.787G>A (p.A263T) alteration is located in exon 1 (coding exon 1) of the CHRM4 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the alanine (A) at amino acid position 263 to be replaced by a threonine (T). 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

0.071

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

2.2

DANN

Benign

0.84

DEOGEN2

Benign

0.094

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.38

M_CAP

Benign

0.049

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.47

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.20

REVEL

Benign

0.019

Sift

Benign

0.55

Sift4G

Benign

0.64

Polyphen

0.0080

Vest4

0.039

MutPred

0.43

Gain of phosphorylation at A263 (P = 0.0031);

MVP

0.47

MPC

0.94

ClinPred

0.040

GERP RS

-1.3

Varity_R

0.021

gMVP

0.21

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