Genetic Variant CHRM4:c.*175G>A (chr11-46384943-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000741.5(CHRM4):c.*175G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 645,342 control chromosomes in the GnomAD database, including 141 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 0.016 ( 22 hom., cov: 33)

Exomes 𝑓: 0.020 ( 119 hom. )

Consequence

CHRM4
NM_000741.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.86

Publications

3 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=-0.6).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (2454/152352) while in subpopulation NFE AF = 0.0219 (1492/68028). AF 95% confidence interval is 0.021. There are 22 homozygotes in GnomAd4. There are 1264 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM4	NM_000741.5 link	c.*175G>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000682254.1	NP_000732.2	P08173
CHRM4	NM_001366692.2 link	c.*175G>A		3_prime_UTR_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.*175G>A		3_prime_UTR_variant	Exon 2 of 2		NM_000741.5	ENSP00000507561.1		P08173
CHRM4	ENST00000433765.3 link	c.*175G>A		downstream_gene_variant		6		ENSP00000409378.2		P08173

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

2456

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0429

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0219

Gnomad OTH

AF:

0.0143

GnomAD4 exome

AF:

0.0196

AC:

9643

AN:

492990

Hom.:

119

AF XY:

0.0196

AC XY:

4534

AN XY:

231106

show subpopulations

African (AFR)

AF:

0.00154

AC:

AN:

9114

American (AMR)

AF:

0.00178

AC:

AN:

562

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

2996

East Asian (EAS)

AF:

0.00

AC:

AN:

2092

South Asian (SAS)

AF:

0.000725

AC:

AN:

9652

European-Finnish (FIN)

AF:

0.0130

AC:

AN:

154

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

990

European-Non Finnish (NFE)

AF:

0.0207

AC:

9355

AN:

451508

Other (OTH)

AF:

0.0155

AC:

247

AN:

15922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

461

922

1382

1843

2304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.0161

AC:

2454

AN:

152352

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1264

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00375

AC:

156

AN:

41596

American (AMR)

AF:

0.0199

AC:

305

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0429

AC:

455

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0219

AC:

1492

AN:

68028

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0209

Hom.:

Bravo

AF:

0.0135

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.79

(source)

DANN

Benign

0.84

PhyloP100

-1.9

Splicing

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