15-78601287-G-A

Variant names:

• chr15-78601287-G-A
• rs1419481900
• NM_000743.5:c.1355C>T

Variant summary

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

The NM_000743.5(CHRNA3):​c.1355C>T​(p.Ala452Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89

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, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.1355C>T	p.Ala452Val	missense_variant	Exon 5 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.1355C>T	p.Ala452Val	missense_variant	Exon 5 of 6		NP_001160166.1
CHRNA3	XM_006720382.4	c.1154C>T	p.Ala385Val	missense_variant	Exon 5 of 6		XP_006720445.1
CHRNA3	NR_046313.2	n.1557C>T		non_coding_transcript_exon_variant	Exon 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1355C>T	p.Ala452Val	missense_variant	Exon 5 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1355C>T	p.Ala452Val	missense_variant	Exon 5 of 6	1		ENSP00000267951.4
CHRNA3	ENST00000559658.5	n.1355C>T		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.78		Gain of ubiquitination at K449 (P = 0.0635);Gain of ubiquitination at K449 (P = 0.0635);
MVP		0.95
MPC		0.85
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.68

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: rs1419481900; hg19: chr15-78893629;