rs3738435

Variant names:

• chr1-239907303-T-C
• rs3738435
• NM_001375978.1:c.-19-130T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-239907303-T-C
• chr1-239907303-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001375978.1(CHRM3):​c.-19-130T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 640,720 control chromosomes in the GnomAD database, including 16,321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4334 hom., cov: 32)
  • Exomes 𝑓: 0.22 (11987 hom.)
• Consequence: CHRM3 NM_001375978.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 10 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-239907303-T-C is Benign according to our data. Variant chr1-239907303-T-C is described in ClinVar as [Benign]. Clinvar id is 1253741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRM3	NM_001375978.1	c.-19-130T>C		intron_variant	Intron 6 of 6	ENST00000676153.1	NP_001362907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRM3	ENST00000676153.1	c.-19-130T>C		intron_variant	Intron 6 of 6		NM_001375978.1	ENSP00000502667.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35639 AN: 151994 Hom.: 4323 Cov.: 32

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.216 AC: 105780 AN: 488608 Hom.: 11987 AF XY: 0.215 AC XY: 54983 AN XY: 255618

African (AFR) AF: 0.271 AC: 3561 AN: 13126

American (AMR) AF: 0.276 AC: 5017 AN: 18180

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 3081 AN: 13864

East Asian (EAS) AF: 0.318 AC: 9947 AN: 31244

South Asian (SAS) AF: 0.199 AC: 8969 AN: 45064

European-Finnish (FIN) AF: 0.223 AC: 7149 AN: 32002

Middle Eastern (MID) AF: 0.242 AC: 719 AN: 2976

European-Non Finnish (NFE) AF: 0.200 AC: 61065 AN: 304798

Other (OTH) AF: 0.229 AC: 6272 AN: 27354

GnomAD4 genome AF: 0.235 AC: 35683 AN: 152112 Hom.: 4334 Cov.: 32 AF XY: 0.234 AC XY: 17399 AN XY: 74368

African (AFR) AF: 0.273 AC: 11313 AN: 41482

American (AMR) AF: 0.254 AC: 3881 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1959 AN: 5170

South Asian (SAS) AF: 0.212 AC: 1024 AN: 4824

European-Finnish (FIN) AF: 0.220 AC: 2333 AN: 10594

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13629 AN: 67974

Other (OTH) AF: 0.254 AC: 536 AN: 2114

Alfa AF: 0.226 Hom.: 1675

Bravo AF: 0.242

Asia WGS AF: 0.299 AC: 1038 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17130513) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.79
DANN	Benign	0.24
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3738435; hg19: chr1-240070603; COSMIC: COSV55086380;