15-78596663-A-T
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000743.5(CHRNA3):c.1459T>A(p.Cys487Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,036 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: 0.0000021 ( 0 hom. )
Consequence
CHRNA3
NM_000743.5 missense
NM_000743.5 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 9.30
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.886
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA3 | NM_000743.5 | c.1459T>A | p.Cys487Ser | missense_variant | 6/6 | ENST00000326828.6 | NP_000734.2 | |
CHRNA3 | XM_006720382.4 | c.1258T>A | p.Cys420Ser | missense_variant | 6/6 | XP_006720445.1 | ||
CHRNA3 | NM_001166694.2 | c.1390-3472T>A | intron_variant | NP_001160166.1 | ||||
CHRNA3 | NR_046313.2 | n.1661T>A | non_coding_transcript_exon_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNA3 | ENST00000326828.6 | c.1459T>A | p.Cys487Ser | missense_variant | 6/6 | 1 | NM_000743.5 | ENSP00000315602 | P1 | |
CHRNA3 | ENST00000348639.7 | c.1390-3472T>A | intron_variant | 1 | ENSP00000267951 | |||||
CHRNA3 | ENST00000559002.5 | n.70T>A | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
CHRNA3 | ENST00000559658.5 | c.1459T>A | p.Cys487Ser | missense_variant, NMD_transcript_variant | 6/8 | 2 | ENSP00000452896 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250236Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135356
GnomAD3 exomes
AF:
AC:
1
AN:
250236
Hom.:
AF XY:
AC XY:
0
AN XY:
135356
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461036Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726868
GnomAD4 exome
AF:
AC:
3
AN:
1461036
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
726868
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ExAC
AF:
AC:
2
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 | May 03, 2022 | Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant has not been reported in the literature in individuals affected with CHRNA3-related conditions. This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 487 of the CHRNA3 protein (p.Cys487Ser). This variant is present in population databases (rs772596477, gnomAD 0.003%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Gain of glycosylation at C487 (P = 0.1292);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at