chr1-239907644-G-A

Position:

• chr1-239907644-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001375978.1(CHRM3):​c.193G>A​(p.Val65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,614,116 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 32)
  • Exomes 𝑓: 0.016 (259 hom.)
• Consequence: CHRM3 NM_001375978.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0850

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00343284).
• BP6: Variant 1-239907644-G-A is Benign according to our data. Variant chr1-239907644-G-A is described in ClinVar as [Benign]. Clinvar id is 1576872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-239907644-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0135 (2055/152230) while in subpopulation SAS AF= 0.0375 (181/4824). AF 95% confidence interval is 0.0331. There are 28 homozygotes in gnomad4. There are 1103 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRM3	NM_001375978.1	c.193G>A	p.Val65Ile	missense_variant	7/7	ENST00000676153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRM3	ENST00000676153.1	c.193G>A	p.Val65Ile	missense_variant	7/7		NM_001375978.1	P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2054 AN: 152112 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00837

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0174 AC: 4386 AN: 251400 Hom.: 62 AF XY: 0.0197 AC XY: 2683 AN XY: 135870

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00804

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.0414

Gnomad FIN exome AF: 0.0431

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0158 AC: 23099 AN: 1461886 Hom.: 259 Cov.: 31 AF XY: 0.0168 AC XY: 12200 AN XY: 727242

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00872

Gnomad4 EAS exome AF: 0.00202

Gnomad4 SAS exome AF: 0.0431

Gnomad4 FIN exome AF: 0.0421

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0145

GnomAD4 genome AF: 0.0135 AC: 2055 AN: 152230 Hom.: 28 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74440

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00837

Gnomad4 EAS AF: 0.00522

Gnomad4 SAS AF: 0.0375

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0137 Hom.: 30

Bravo AF: 0.00861

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0148 AC: 57

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.0180 AC: 2188

Asia WGS AF: 0.0140 AC: 49 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CHRM3: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.28
DANN	Benign	0.77
DEOGEN2	Benign	0.060	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.70	.;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.26	N;.;N
REVEL	Benign	0.086
Sift	Benign	0.49	T;.;T
Sift4G	Benign	0.084	T;T;D
Polyphen		0.0020	B;B;.
Vest4		0.021
MPC		0.39
ClinPred		0.0023	T
GERP RS		-11
Varity_R		0.025
gMVP		0.38

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

Other links and lift over

dbSNP: rs2067481; hg19: chr1-240070944; COSMIC: COSV55091298;