Genetic Variant NM_000741.5:c.987G>C (chr11-46385571-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000741.5(CHRM4):c.987G>C(p.Gln329His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CHRM4
NM_000741.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.218

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09788445).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000741.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM4	NM_000741.5	MANE Select	c.987G>C	p.Gln329His	missense	Exon 2 of 2	NP_000732.2
	CHRM4	NM_001366692.2		c.987G>C	p.Gln329His	missense	Exon 2 of 2	NP_001353621.1	P08173

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRM4	ENST00000682254.1	MANE Select	c.987G>C	p.Gln329His	missense	Exon 2 of 2	ENSP00000507561.1	P08173
CHRM4	ENST00000433765.3	TSL:6	c.987G>C	p.Gln329His	missense	Exon 1 of 1	ENSP00000409378.2	P08173
CHRM4	ENST00000855139.1		c.987G>C	p.Gln329His	missense	Exon 2 of 2	ENSP00000525198.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000469

AC:

AN:

213214

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000322

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692794

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32450

American (AMR)

AF:

0.0000243

AC:

AN:

41180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22766

East Asian (EAS)

AF:

0.00

AC:

AN:

39008

South Asian (SAS)

AF:

0.00

AC:

AN:

78086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080596

Other (OTH)

AF:

0.00

AC:

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.16

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.51

M_CAP

Benign

0.033

MetaRNN

Benign

0.098

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.060

PhyloP100

0.22

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.0

REVEL

Benign

0.017

Sift

Benign

0.19

Sift4G

Benign

0.13

Polyphen

0.010

Vest4

0.077

MutPred

0.32

Loss of MoRF binding (P = 0.1143)

MVP

0.47

MPC

0.81

ClinPred

0.031

GERP RS

2.3

Varity_R

0.080

gMVP

0.43

Mutation Taster

=90/10

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over