rs552730458

Variant names:

• chr11-46385705-G-A
• rs552730458
• NM_000741.5:c.853C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

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. 15/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27987844).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.853C>T	p.Arg285Cys	missense	Exon 2 of 2	NP_000732.2
	CHRM4	NM_001366692.2		c.853C>T	p.Arg285Cys	missense	Exon 2 of 2	NP_001353621.1	P08173

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRM4	ENST00000682254.1	MANE Select	c.853C>T	p.Arg285Cys	missense	Exon 2 of 2	ENSP00000507561.1	P08173
	CHRM4	ENST00000433765.3	TSL:6	c.853C>T	p.Arg285Cys	missense	Exon 1 of 1	ENSP00000409378.2	P08173
	CHRM4	ENST00000855139.1		c.853C>T	p.Arg285Cys	missense	Exon 2 of 2	ENSP00000525198.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152194 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000544 AC: 11 AN: 202332 AF XY: 0.0000549

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.0000241 AC: 34 AN: 1408370 Hom.: 0 Cov.: 32 AF XY: 0.0000230 AC XY: 16 AN XY: 695870

African (AFR) AF: 0.00 AC: 0 AN: 31658

American (AMR) AF: 0.0000531 AC: 2 AN: 37654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22380

East Asian (EAS) AF: 0.0000763 AC: 3 AN: 39338

South Asian (SAS) AF: 0.0000385 AC: 3 AN: 77886

European-Finnish (FIN) AF: 0.0000409 AC: 2 AN: 48848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.0000221 AC: 24 AN: 1087236

Other (OTH) AF: 0.00 AC: 0 AN: 57868

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000500 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.076
Eigen_PC	Benign	0.012
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.090	N
PhyloP100		2.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.10	T
Sift4G	Benign	0.072	T
Polyphen		0.99	D
Vest4		0.23
MutPred		0.52		Gain of catalytic residue at V287 (P = 0.0371)
MVP		0.87
MPC		1.2
ClinPred		0.096	T
GERP RS		4.1
Varity_R		0.079
gMVP		0.26
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs552730458; hg19: chr11-46407255;