chr15-78596650-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000743.5(CHRNA3):c.1472C>T(p.Thr491Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CHRNA3
NM_000743.5 missense
NM_000743.5 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 9.97
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.98
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHRNA3 | NM_000743.5 | c.1472C>T | p.Thr491Ile | missense_variant | 6/6 | ENST00000326828.6 | |
CHRNA3 | XM_006720382.4 | c.1271C>T | p.Thr424Ile | missense_variant | 6/6 | ||
CHRNA3 | NM_001166694.2 | c.1390-3459C>T | intron_variant | ||||
CHRNA3 | NR_046313.2 | n.1674C>T | non_coding_transcript_exon_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHRNA3 | ENST00000326828.6 | c.1472C>T | p.Thr491Ile | missense_variant | 6/6 | 1 | NM_000743.5 | P1 | |
CHRNA3 | ENST00000348639.7 | c.1390-3459C>T | intron_variant | 1 | |||||
CHRNA3 | ENST00000559002.5 | n.83C>T | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
CHRNA3 | ENST00000559658.5 | c.1472C>T | p.Thr491Ile | missense_variant, NMD_transcript_variant | 6/8 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249476Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134988
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460174Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726446
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GnomAD4 genome ? Cov.: 32
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?
Cov.:
32
ExAC
?
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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 | GeneDx | Oct 26, 2016 | The T491I variant in the CHRNA3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T491I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T491I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T491I as a variant of uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at L496 (P = 0.0315);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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