NM_000743.5:c.268-5C>T

Variant names:

• chr15-78617138-G-A
• rs3743074
• NM_000743.5:c.268-5C>T

Variant summary

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

The NM_000743.5(CHRNA3):​c.268-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.629 in 1,587,198 control chromosomes in the GnomAD database, including 316,958 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29885 hom., cov: 32)
  • Exomes 𝑓: 0.63 (287073 hom.)
• Consequence: CHRNA3 NM_000743.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001611
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0270
• Publications: 41 publications found

Genes affected

CHRNA3 (HGNC:1957): (cholinergic receptor nicotinic alpha 3 subunit) This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

CHRNA3 Gene-Disease associations (from GenCC):

• urinary bladder, atony of

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-78617138-G-A is Benign according to our data. Variant chr15-78617138-G-A is described in ClinVar as Benign. ClinVar VariationId is 1209768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000743.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA3	NM_000743.5	MANE Select	c.268-5C>T		splice_region intron	N/A	NP_000734.2
	CHRNA3	NM_001166694.2		c.268-5C>T		splice_region intron	N/A	NP_001160166.1
	CHRNA3	NR_046313.2		n.470-5C>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.268-5C>T		splice_region intron	N/A	ENSP00000315602.5
	CHRNA3	ENST00000348639.7	TSL:1	c.268-5C>T		splice_region intron	N/A	ENSP00000267951.4
	CHRNA3	ENST00000559658.5	TSL:2	n.268-5C>T		splice_region intron	N/A	ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94691 AN: 151890 Hom.: 29847 Cov.: 32

Gnomad AFR AF: 0.561

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.637

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.790

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.651

GnomAD2 exomes AF: 0.660 AC: 163858 AN: 248206 AF XY: 0.659

Gnomad AFR exome AF: 0.565

Gnomad AMR exome AF: 0.837

Gnomad ASJ exome AF: 0.655

Gnomad EAS exome AF: 0.562

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.627

Gnomad OTH exome AF: 0.659

GnomAD4 exome AF: 0.630 AC: 904076 AN: 1435190 Hom.: 287073 Cov.: 26 AF XY: 0.631 AC XY: 451579 AN XY: 715342

African (AFR) AF: 0.567 AC: 18687 AN: 32958

American (AMR) AF: 0.827 AC: 36709 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 16625 AN: 25918

East Asian (EAS) AF: 0.577 AC: 22813 AN: 39566

South Asian (SAS) AF: 0.686 AC: 58588 AN: 85412

European-Finnish (FIN) AF: 0.655 AC: 34669 AN: 52950

Middle Eastern (MID) AF: 0.724 AC: 4135 AN: 5710

European-Non Finnish (NFE) AF: 0.619 AC: 674388 AN: 1088806

Other (OTH) AF: 0.630 AC: 37462 AN: 59490

GnomAD4 genome AF: 0.624 AC: 94777 AN: 152008 Hom.: 29885 Cov.: 32 AF XY: 0.625 AC XY: 46447 AN XY: 74298

African (AFR) AF: 0.561 AC: 23237 AN: 41446

American (AMR) AF: 0.751 AC: 11481 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.637 AC: 2209 AN: 3468

East Asian (EAS) AF: 0.562 AC: 2897 AN: 5156

South Asian (SAS) AF: 0.676 AC: 3263 AN: 4828

European-Finnish (FIN) AF: 0.651 AC: 6869 AN: 10558

Middle Eastern (MID) AF: 0.777 AC: 227 AN: 292

European-Non Finnish (NFE) AF: 0.628 AC: 42670 AN: 67962

Other (OTH) AF: 0.656 AC: 1384 AN: 2110

Alfa AF: 0.630 Hom.: 72101

Bravo AF: 0.627

Asia WGS AF: 0.641 AC: 2230 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Urinary bladder, atony of Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.9
DANN	Benign	0.54
PhyloP100		-0.027
Mutation Taster		=53/47	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.052
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: rs3743074; hg19: chr15-78909480; COSMIC: COSV58776490; COSMIC: COSV58776490;