chr15-78596693-G-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000743.5(CHRNA3):c.1429C>A(p.Arg477Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,464 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: 0.0000027 ( 0 hom. )
Consequence
CHRNA3
NM_000743.5 missense
NM_000743.5 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 5.17
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, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA3 | NM_000743.5 | c.1429C>A | p.Arg477Ser | missense_variant | 6/6 | ENST00000326828.6 | NP_000734.2 | |
CHRNA3 | XM_006720382.4 | c.1228C>A | p.Arg410Ser | missense_variant | 6/6 | XP_006720445.1 | ||
CHRNA3 | NM_001166694.2 | c.1390-3502C>A | intron_variant | NP_001160166.1 | ||||
CHRNA3 | NR_046313.2 | n.1631C>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.1429C>A | p.Arg477Ser | missense_variant | 6/6 | 1 | NM_000743.5 | ENSP00000315602 | P1 | |
CHRNA3 | ENST00000348639.7 | c.1390-3502C>A | intron_variant | 1 | ENSP00000267951 | |||||
CHRNA3 | ENST00000559002.5 | n.40C>A | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
CHRNA3 | ENST00000559658.5 | c.1429C>A | p.Arg477Ser | missense_variant, NMD_transcript_variant | 6/8 | 2 | ENSP00000452896 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249190Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134798
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460464Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726578
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2022 | The c.1429C>A (p.R477S) alteration is located in exon 6 (coding exon 6) of the CHRNA3 gene. This alteration results from a C to A substitution at nucleotide position 1429, causing the arginine (R) at amino acid position 477 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
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
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0716);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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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