15-78596626-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_000743.5(CHRNA3):​c.1495del​(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: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CHRNA3
NM_000743.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.187
Variant links:
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.

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
CHRNA3NM_000743.5 linkuse as main transcriptc.1495del p.Leu499Ter frameshift_variant 6/6 ENST00000326828.6 NP_000734.2
CHRNA3XM_006720382.4 linkuse as main transcriptc.1294del p.Leu432Ter frameshift_variant 6/6 XP_006720445.1
CHRNA3NM_001166694.2 linkuse as main transcriptc.1390-3436del intron_variant NP_001160166.1
CHRNA3NR_046313.2 linkuse as main transcriptn.1697del non_coding_transcript_exon_variant 6/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CHRNA3ENST00000326828.6 linkuse as main transcriptc.1495del p.Leu499Ter frameshift_variant 6/61 NM_000743.5 ENSP00000315602 P1P32297-2
CHRNA3ENST00000348639.7 linkuse as main transcriptc.1390-3436del intron_variant 1 ENSP00000267951 P32297-3
CHRNA3ENST00000559002.5 linkuse as main transcriptn.106del non_coding_transcript_exon_variant 1/21
CHRNA3ENST00000559658.5 linkuse as main transcriptc.1495del p.Leu499Ter frameshift_variant, NMD_transcript_variant 6/82 ENSP00000452896 P32297-2

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000613
AC:
15
AN:
244572
Hom.:
0
AF XY:
0.0000605
AC XY:
8
AN XY:
132328
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000928
Gnomad ASJ exome
AF:
0.000408
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000714
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000495
AC:
72
AN:
1455502
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
39
AN XY:
724086
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000706
Gnomad4 ASJ exome
AF:
0.000463
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000217
Hom.:
0
Bravo
AF:
0.0000604
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000178

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 12, 2022This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs759986717; hg19: chr15-78888968; API