11-46385836-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000741.5(CHRM4):c.722C>T(p.Thr241Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000303 in 1,451,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CHRM4 NM_000741.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.34

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CHRM4
• BP4: Computational evidence support a benign effect (MetaRNN=0.202555).
• BS2: High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM4	NM_000741.5	c.722C>T	p.Thr241Met	missense_variant	2/2	ENST00000682254.1
CHRM4	NM_001366692.2	c.722C>T	p.Thr241Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM4	ENST00000682254.1	c.722C>T	p.Thr241Met	missense_variant	2/2		NM_000741.5	P1
CHRM4	ENST00000433765.3	c.722C>T	p.Thr241Met	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000262 AC: 6 AN: 229170 Hom.: 0 AF XY: 0.0000160 AC XY: 2 AN XY: 124888

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: 0.0000345

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000303 AC: 44 AN: 1451176 Hom.: 0 Cov.: 32 AF XY: 0.0000291 AC XY: 21 AN XY: 721082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000588

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000325

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.722C>T (p.T241M) 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 722, causing the threonine (T) at amino acid position 241 to be replaced by a methionine (M). 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	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.95	N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.063	T
Sift4G	Uncertain	0.058	T
Polyphen		0.017	B
Vest4		0.16
MutPred		0.54		Gain of sheet (P = 0.0149);
MVP		0.61
MPC		1.5
ClinPred		0.082	T
GERP RS		3.6
Varity_R		0.058
gMVP		0.32

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

Other links and lift over

dbSNP: rs200827665; hg19: chr11-46407386;