Genetic Variant CHRM4:p.Thr447Thr (chr11-46385217-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000741.5(CHRM4):c.1341C>T(p.Thr447Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.155 in 1,613,938 control chromosomes in the GnomAD database, including 20,553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1551 hom., cov: 33)

Exomes 𝑓: 0.16 ( 19002 hom. )

Consequence

CHRM4
NM_000741.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.74

Publications

19 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM4	NM_000741.5 link	c.1341C>T	p.Thr447Thr	synonymous_variant	Exon 2 of 2	ENST00000682254.1	NP_000732.2	P08173
CHRM4	NM_001366692.2 link	c.1341C>T	p.Thr447Thr	synonymous_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.1341C>T	p.Thr447Thr	synonymous_variant	Exon 2 of 2		NM_000741.5	ENSP00000507561.1		P08173
CHRM4	ENST00000433765.3 link	c.1341C>T	p.Thr447Thr	synonymous_variant	Exon 1 of 1	6		ENSP00000409378.2		P08173

Frequencies

GnomAD3 genomes

AF:

0.139

AC:

21189

AN:

152144

Hom.:

1554

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.108

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.0582

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.117

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.148

GnomAD2 exomes

AF:

0.134

AC:

33632

AN:

250384

AF XY:

0.139

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.0690

Gnomad ASJ exome

AF:

0.162

Gnomad EAS exome

AF:

0.0562

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.167

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.157

AC:

229734

AN:

1461676

Hom.:

19002

Cov.:

AF XY:

0.157

AC XY:

114510

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.105

AC:

3526

AN:

33480

American (AMR)

AF:

0.0734

AC:

3281

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

4239

AN:

26136

East Asian (EAS)

AF:

0.0577

AC:

2292

AN:

39696

South Asian (SAS)

AF:

0.154

AC:

13245

AN:

86258

European-Finnish (FIN)

AF:

0.120

AC:

6379

AN:

53312

Middle Eastern (MID)

AF:

0.193

AC:

1114

AN:

5768

European-Non Finnish (NFE)

AF:

0.168

AC:

186387

AN:

1111928

Other (OTH)

AF:

0.154

AC:

9271

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

13120

26240

39361

52481

65601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6494

12988

19482

25976

32470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.139

AC:

21190

AN:

152262

Hom.:

1551

Cov.:

AF XY:

0.137

AC XY:

10198

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.111

AC:

4621

AN:

41546

American (AMR)

AF:

0.108

AC:

1650

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

548

AN:

3472

East Asian (EAS)

AF:

0.0582

AC:

302

AN:

5192

South Asian (SAS)

AF:

0.147

AC:

712

AN:

4828

European-Finnish (FIN)

AF:

0.117

AC:

1242

AN:

10612

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.169

AC:

11518

AN:

68008

Other (OTH)

AF:

0.145

AC:

306

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

972

1945

2917

3890

4862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.153

Hom.:

840

Bravo

AF:

0.136

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.162

EpiControl

AF:

0.166

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

9.4

(source)

DANN

Benign

0.90

PhyloP100

5.7

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over