NM_000743.5:c.1495delC

Variant names:

• chr15-78596626-AG-A
• rs759986717
• NM_000743.5:c.1495delC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000743.5(CHRNA3):​c.1495delC​(p.Leu499fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000516 in 1,607,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CHRNA3 NM_000743.5 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.187

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0152 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.1495delC	p.Leu499fs	frameshift_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.1294delC	p.Leu432fs	frameshift_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-3436delC		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1697delC		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1495delC	p.Leu499fs	frameshift_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-3436delC		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.106delC		non_coding_transcript_exon_variant	Exon 1 of 2	1
CHRNA3	ENST00000559658.5	n.1495delC		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000613 AC: 15 AN: 244572 Hom.: 0 AF XY: 0.0000605 AC XY: 8 AN XY: 132328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000928

Gnomad ASJ exome AF: 0.000408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000495 AC: 72 AN: 1455502 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 39 AN XY: 724086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000706

Gnomad4 ASJ exome AF: 0.000463

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3;C5231389:Urinary bladder, atony of Uncertain:1

Apr 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs759986717, gnomAD 0.04%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with CHRNA3-related conditions. This sequence change creates a premature translational stop signal (p.Leu499*) in the CHRNA3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the CHRNA3 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs759986717; hg19: chr15-78888968;