15-78601290-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 1P and 17B. PP3 BP4 BP6_Very_Strong BS1 BS2

The NM_000743.5(CHRNA3):c.1352T>C(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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]

ACMG classification

Verdict is Benign. Variant got -16 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_multiple_submitters_no_conflicts, 2 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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA3	NM_000743.5	c.1352T>C	p.Ile451Thr	missense_variant	5/6	ENST00000326828.6
CHRNA3	NM_001166694.2	c.1352T>C	p.Ile451Thr	missense_variant	5/6
CHRNA3	XM_006720382.4	c.1151T>C	p.Ile384Thr	missense_variant	5/6
CHRNA3	NR_046313.2	n.1554T>C		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1352T>C	p.Ile451Thr	missense_variant	5/6	1	NM_000743.5	P1
CHRNA3	ENST00000348639.7	c.1352T>C	p.Ile451Thr	missense_variant	5/6	1
CHRNA3	ENST00000559658.5	c.1352T>C	p.Ile451Thr	missense_variant, NMD_transcript_variant	5/8	2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000458 AC: 115 AN: 251206 Hom.: 2 AF XY: 0.000670 AC XY: 91 AN XY: 135766

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000268 AC: 392 AN: 1461840 Hom.: 3 Cov.: 31 AF XY: 0.000380 AC XY: 276 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00443

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74370

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000453 AC: 55

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

- -

CHRNA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.84		Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);
MVP		0.98
MPC		1.0
ClinPred		0.36	T
GERP RS		5.6
Varity_R		0.80
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs200681637; hg19: chr15-78893632;