15-78596644-C-G

Variant names:

• chr15-78596644-C-G
• rs201438830
• NM_000743.5:c.1478G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000743.5(CHRNA3):​c.1478G>C​(p.Gly493Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,611,408 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.69

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 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, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.1478G>C	p.Gly493Ala	missense_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.1277G>C	p.Gly426Ala	missense_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-3453G>C		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1680G>C		non_coding_transcript_exon_variant	Exon 6 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1478G>C	p.Gly493Ala	missense_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-3453G>C		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.89G>C		non_coding_transcript_exon_variant	Exon 1 of 2	1
CHRNA3	ENST00000559658.5	n.1478G>C		non_coding_transcript_exon_variant	Exon 6 of 8	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459248 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726022

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1478G>C (p.G493A) alteration is located in exon 6 (coding exon 6) of the CHRNA3 gene. This alteration results from a G to C substitution at nucleotide position 1478, causing the glycine (G) at amino acid position 493 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3;C5231389:Urinary bladder, atony of Uncertain:1

Mar 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.68
Sift	Benign	0.15	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.73		Gain of catalytic residue at G493 (P = 0.0817);
MVP		0.89
MPC		0.94
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.41
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs201438830; hg19: chr15-78888986;