15-78596626-AG-A
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000743.5(CHRNA3):βc.1495delβ(p.Leu499Ter) 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 (β ).
Frequency
Genomes: π 0.000072 ( 0 hom., cov: 32)
Exomes π: 0.000049 ( 0 hom. )
Consequence
CHRNA3
NM_000743.5 frameshift
NM_000743.5 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA3 | NM_000743.5 | c.1495del | p.Leu499Ter | frameshift_variant | 6/6 | ENST00000326828.6 | NP_000734.2 | |
CHRNA3 | XM_006720382.4 | c.1294del | p.Leu432Ter | frameshift_variant | 6/6 | XP_006720445.1 | ||
CHRNA3 | NM_001166694.2 | c.1390-3436del | intron_variant | NP_001160166.1 | ||||
CHRNA3 | NR_046313.2 | n.1697del | non_coding_transcript_exon_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNA3 | ENST00000326828.6 | c.1495del | p.Leu499Ter | frameshift_variant | 6/6 | 1 | NM_000743.5 | ENSP00000315602 | P1 | |
CHRNA3 | ENST00000348639.7 | c.1390-3436del | intron_variant | 1 | ENSP00000267951 | |||||
CHRNA3 | ENST00000559002.5 | n.106del | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
CHRNA3 | ENST00000559658.5 | c.1495del | p.Leu499Ter | frameshift_variant, NMD_transcript_variant | 6/8 | 2 | ENSP00000452896 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000613 AC: 15AN: 244572Hom.: 0 AF XY: 0.0000605 AC XY: 8AN XY: 132328
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GnomAD4 exome AF: 0.0000495 AC: 72AN: 1455502Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 39AN XY: 724086
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74364
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 12, 2022 | 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. This variant is present in population databases (rs759986717, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CHRNA3-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at