Genetic Variant NM_000738.3:c.1353C>T (chr11-62909748-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000738.3(CHRM1):c.1353C>T(p.Ser451Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,614,016 control chromosomes in the GnomAD database, including 8,408 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 0.088 ( 940 hom., cov: 33)

Exomes 𝑓: 0.092 ( 7468 hom. )

Consequence

CHRM1
NM_000738.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.851

Publications

13 publications found

Variant links:

Genes affected

CHRM1 (HGNC:1950): (cholinergic receptor muscarinic 1) 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 muscarinic cholinergic receptor 1 is involved in mediation of vagally-induced bronchoconstriction and in the acid secretion of the gastrointestinal tract. The gene encoding this receptor is localized to 11q13. [provided by RefSeq, Jul 2008]

CHRM1 Gene-Disease associations (from GenCC):

intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: G2P

CHRM1 links:

ENSG00000257002 (HGNC:58194):

ENSG00000257002 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP7

Synonymous conserved (PhyloP=-0.851 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM1	NM_000738.3 link	c.1353C>T	p.Ser451Ser	synonymous_variant	Exon 2 of 2	ENST00000306960.4	NP_000729.2	P11229-1Q53XZ3
CHRM1	XM_011544742.3 link	c.1353C>T	p.Ser451Ser	synonymous_variant	Exon 2 of 2		XP_011543044.1	P11229-1Q53XZ3
CHRM1-AS1	NR_199052.1 link	n.209+133G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM1	ENST00000306960.4 link	c.1353C>T	p.Ser451Ser	synonymous_variant	Exon 2 of 2	1	NM_000738.3	ENSP00000306490.3		P11229-1

Frequencies

GnomAD3 genomes

AF:

0.0882

AC:

13421

AN:

152222

Hom.:

938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0202

Gnomad AMI

AF:

0.144

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.0904

Gnomad EAS

AF:

0.0898

Gnomad SAS

AF:

0.0347

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0909

Gnomad OTH

AF:

0.0889

GnomAD2 exomes

AF:

0.111

AC:

27895

AN:

250728

AF XY:

0.104

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.0881

Gnomad EAS exome

AF:

0.0937

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.0926

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.0917

AC:

134091

AN:

1461676

Hom.:

7468

Cov.:

AF XY:

0.0902

AC XY:

65619

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0178

AC:

596

AN:

33480

American (AMR)

AF:

0.272

AC:

12155

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0901

AC:

2355

AN:

26136

East Asian (EAS)

AF:

0.0814

AC:

3232

AN:

39700

South Asian (SAS)

AF:

0.0377

AC:

3256

AN:

86252

European-Finnish (FIN)

AF:

0.141

AC:

7540

AN:

53372

Middle Eastern (MID)

AF:

0.0980

AC:

565

AN:

5768

European-Non Finnish (NFE)

AF:

0.0893

AC:

99263

AN:

1111866

Other (OTH)

AF:

0.0849

AC:

5129

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

7598

15197

22795

30394

37992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3664

7328

10992

14656

18320

<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:

0.0882

AC:

13438

AN:

152340

Hom.:

940

Cov.:

AF XY:

0.0940

AC XY:

7002

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0201

AC:

838

AN:

41590

American (AMR)

AF:

0.232

AC:

3553

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0904

AC:

314

AN:

3472

East Asian (EAS)

AF:

0.0904

AC:

468

AN:

5176

South Asian (SAS)

AF:

0.0345

AC:

167

AN:

4834

European-Finnish (FIN)

AF:

0.146

AC:

1552

AN:

10622

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0909

AC:

6184

AN:

68030

Other (OTH)

AF:

0.0918

AC:

194

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

630

1261

1891

2522

3152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<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:

0.0850

Hom.:

275

Bravo

AF:

0.0930

Asia WGS

AF:

0.0690

AC:

240

AN:

3478

EpiCase

AF:

0.0884

EpiControl

AF:

0.0818

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.0

(source)

DANN

Benign

0.90

PhyloP100

-0.85

Mutation Taster

=99/1

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