Genetic Variant NM_000741.5:c.722C>T (chr11-46385836-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.202555).

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM4	NM_000741.5 link	c.722C>T	p.Thr241Met	missense_variant	Exon 2 of 2	ENST00000682254.1	NP_000732.2	P08173
CHRM4	NM_001366692.2 link	c.722C>T	p.Thr241Met	missense_variant	Exon 2 of 2		NP_001353621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM4	ENST00000682254.1 link	c.722C>T	p.Thr241Met	missense_variant	Exon 2 of 2		NM_000741.5	ENSP00000507561.1		P08173
CHRM4	ENST00000433765.3 link	c.722C>T	p.Thr241Met	missense_variant	Exon 1 of 1	6		ENSP00000409378.2		P08173

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000262

AC:

AN:

229170

Hom.:

AF XY:

0.0000160

AC XY:

AN XY:

124888

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:

0.0000345

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1451176

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

721082

show subpopulations

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.18

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.050

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

REVEL

Benign

0.15

Sift

Benign

0.063

Sift4G

Uncertain

0.058

Polyphen

0.017

Vest4

0.16

MutPred

0.54

Gain of sheet (P = 0.0149);

MVP

0.61

MPC

1.5

ClinPred

0.082

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

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