15-78601997-G-T

Variant names:

• chr15-78601997-G-T
• NM_000743.5:c.645C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000743.5(CHRNA3):​c.645C>A​(p.Tyr215*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA3 NM_000743.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.50

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.575 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.645C>A	p.Tyr215*	stop_gained	Exon 5 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.645C>A	p.Tyr215*	stop_gained	Exon 5 of 6		NP_001160166.1
CHRNA3	XM_006720382.4	c.444C>A	p.Tyr148*	stop_gained	Exon 5 of 6		XP_006720445.1
CHRNA3	NR_046313.2	n.847C>A		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.645C>A	p.Tyr215*	stop_gained	Exon 5 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.645C>A	p.Tyr215*	stop_gained	Exon 5 of 6	1		ENSP00000267951.4
CHRNA3	ENST00000558903.1	n.352C>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
CHRNA3	ENST00000559658.5	n.645C>A		non_coding_transcript_exon_variant	Exon 5 of 8	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.90
GERP RS		5.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-78894339;