rs3743075

Positions:

• chr15-78617110-T-A
• chr15-78617110-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000743.5(CHRNA3):​c.291A>T​(p.Lys97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.731

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.291A>T	p.Lys97Asn	missense_variant	4/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.291A>T	p.Lys97Asn	missense_variant	4/6		NP_001160166.1
CHRNA3	XM_006720382.4	c.90A>T	p.Lys30Asn	missense_variant	4/6		XP_006720445.1
CHRNA3	NR_046313.2	n.493A>T		non_coding_transcript_exon_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.291A>T	p.Lys97Asn	missense_variant	4/6	1	NM_000743.5	ENSP00000315602	P1
CHRNA3	ENST00000348639.7	c.291A>T	p.Lys97Asn	missense_variant	4/6	1		ENSP00000267951
CHRNA3	ENST00000559658.5	c.291A>T	p.Lys97Asn	missense_variant, NMD_transcript_variant	4/8	2		ENSP00000452896

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250308 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.0097	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D
Eigen	Benign	-0.087
Eigen_PC	Benign	0.0099
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.0023	P;P
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.063	T;T
Polyphen		0.65	P;P
Vest4		0.42
MutPred		0.61		Loss of ubiquitination at K97 (P = 0.0218);Loss of ubiquitination at K97 (P = 0.0218);
MVP		0.76
MPC		0.56
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.49
gMVP		0.46

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: rs3743075; hg19: chr15-78909452;