rs3743074

Positions:

• chr15-78617138-G-A
• chr15-78617138-G-T

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001611
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0270

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA3	NM_000743.5	c.268-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000326828.6
CHRNA3	NM_001166694.2	c.268-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CHRNA3	XM_006720382.4	c.67-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CHRNA3	NR_046313.2	n.470-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA3	ENST00000326828.6	c.268-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000743.5	P1
CHRNA3	ENST00000348639.7	c.268-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
CHRNA3	ENST00000559658.5	c.268-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2

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

GnomAD3 exomes AF: 0.660 AC: 163858 AN: 248206 Hom.: 54974 AF XY: 0.659 AC XY: 88433 AN XY: 134094

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 SAS exome AF: 0.695

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

Gnomad4 AFR exome AF: 0.567

Gnomad4 AMR exome AF: 0.827

Gnomad4 ASJ exome AF: 0.641

Gnomad4 EAS exome AF: 0.577

Gnomad4 SAS exome AF: 0.686

Gnomad4 FIN exome AF: 0.655

Gnomad4 NFE exome AF: 0.619

Gnomad4 OTH exome AF: 0.630

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

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.637

Gnomad4 EAS AF: 0.562

Gnomad4 SAS AF: 0.676

Gnomad4 FIN AF: 0.651

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.656

Alfa AF: 0.633 Hom.: 44331

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

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	-	- -

Urinary bladder, atony of Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.9
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs3743074; hg19: chr15-78909480; COSMIC: COSV58776490; COSMIC: COSV58776490;