15-78601290-A-G
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Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3BP4BP6_ModerateBS1BS2
The NM_000743.5(CHRNA3):āc.1352T>Cā(p.Ile451Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,076 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 31)
Exomes š: 0.00027 ( 3 hom. )
Consequence
CHRNA3
NM_000743.5 missense
NM_000743.5 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 9.22
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 Benign. Variant got -10 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.39375237).
BP6
Variant 15-78601290-A-G is Benign according to our data. Variant chr15-78601290-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2182780.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000591 (9/152236) while in subpopulation SAS AF= 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRNA3 | NM_000743.5 | c.1352T>C | p.Ile451Thr | missense_variant | 5/6 | ENST00000326828.6 | NP_000734.2 | |
CHRNA3 | NM_001166694.2 | c.1352T>C | p.Ile451Thr | missense_variant | 5/6 | NP_001160166.1 | ||
CHRNA3 | XM_006720382.4 | c.1151T>C | p.Ile384Thr | missense_variant | 5/6 | XP_006720445.1 | ||
CHRNA3 | NR_046313.2 | n.1554T>C | non_coding_transcript_exon_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHRNA3 | ENST00000326828.6 | c.1352T>C | p.Ile451Thr | missense_variant | 5/6 | 1 | NM_000743.5 | ENSP00000315602 | P1 | |
CHRNA3 | ENST00000348639.7 | c.1352T>C | p.Ile451Thr | missense_variant | 5/6 | 1 | ENSP00000267951 | |||
CHRNA3 | ENST00000559658.5 | c.1352T>C | p.Ile451Thr | missense_variant, NMD_transcript_variant | 5/8 | 2 | ENSP00000452896 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000458 AC: 115AN: 251206Hom.: 2 AF XY: 0.000670 AC XY: 91AN XY: 135766
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GnomAD4 exome AF: 0.000268 AC: 392AN: 1461840Hom.: 3 Cov.: 31 AF XY: 0.000380 AC XY: 276AN XY: 727224
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9AN XY: 74370
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ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | - - |
CHRNA3-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);
MVP
MPC
1.0
ClinPred
T
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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