chr1-239907551-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001375978.1(CHRM3):​c.100G>A​(p.Val34Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CHRM3
NM_001375978.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.264

Publications

3 publications found
Variant links:
Genes affected
CHRM3 (HGNC:1952): (cholinergic receptor muscarinic 3) 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 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]
CHRM3-AS1 (HGNC:40150): (CHRM3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.057323724).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRM3NM_001375978.1 linkc.100G>A p.Val34Ile missense_variant Exon 7 of 7 ENST00000676153.1 NP_001362907.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRM3ENST00000676153.1 linkc.100G>A p.Val34Ile missense_variant Exon 7 of 7 NM_001375978.1 ENSP00000502667.1 P20309

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152096
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251428
AF XY:
0.0000368
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000369
AC:
54
AN:
1461886
Hom.:
0
Cov.:
31
AF XY:
0.0000440
AC XY:
32
AN XY:
727244
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.0000504
AC:
2
AN:
39698
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000432
AC:
48
AN:
1112008
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000197
AC:
3
AN:
152096
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74296
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41400
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.558
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000282
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 01, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.100G>A (p.V34I) alteration is located in exon 5 (coding exon 1) of the CHRM3 gene. This alteration results from a G to A substitution at nucleotide position 100, causing the valine (V) at amino acid position 34 to be replaced by an isoleucine (I). 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
0.072
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
8.9
DANN
Benign
0.94
DEOGEN2
Benign
0.055
T;T;.
Eigen
Benign
-0.92
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.29
.;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.057
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;N;.
PhyloP100
0.26
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.060
N;.;N
REVEL
Benign
0.084
Sift
Benign
0.24
T;.;T
Sift4G
Benign
0.59
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.046
MutPred
0.14
Loss of disorder (P = 0.1538);Loss of disorder (P = 0.1538);Loss of disorder (P = 0.1538);
MVP
0.16
MPC
0.39
ClinPred
0.017
T
GERP RS
2.0
Varity_R
0.039
gMVP
0.49
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs201042655; hg19: chr1-240070851; COSMIC: COSV55079216; API