rs4887069

Variant names:

• chr15-78616728-A-G
• rs4887069
• NM_000743.5:c.377+296T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000743.5(CHRNA3):​c.377+296T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,838 control chromosomes in the GnomAD database, including 8,208 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (8208 hom., cov: 31)
• Consequence: CHRNA3 NM_000743.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• Publications: 22 publications found

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]

CHRNA3 Gene-Disease associations (from GenCC):

• urinary bladder, atony of

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.377+296T>C		intron_variant	Intron 4 of 5	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.377+296T>C		intron_variant	Intron 4 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.579+296T>C		intron_variant	Intron 4 of 7
CHRNA3	XM_006720382.4	c.176+296T>C		intron_variant	Intron 4 of 5		XP_006720445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.377+296T>C		intron_variant	Intron 4 of 5	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.377+296T>C		intron_variant	Intron 4 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559658.5	n.377+296T>C		intron_variant	Intron 4 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46241 AN: 151720 Hom.: 8182 Cov.: 31

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.304

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.305 AC: 46307 AN: 151838 Hom.: 8208 Cov.: 31 AF XY: 0.314 AC XY: 23264 AN XY: 74202

African (AFR) AF: 0.300 AC: 12401 AN: 41376

American (AMR) AF: 0.483 AC: 7374 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 865 AN: 3468

East Asian (EAS) AF: 0.712 AC: 3656 AN: 5134

South Asian (SAS) AF: 0.456 AC: 2200 AN: 4820

European-Finnish (FIN) AF: 0.295 AC: 3109 AN: 10536

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15798 AN: 67930

Other (OTH) AF: 0.312 AC: 659 AN: 2114

Alfa AF: 0.269 Hom.: 1309

Bravo AF: 0.321

Asia WGS AF: 0.580 AC: 2013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.28
DANN	Benign	0.51
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4887069; hg19: chr15-78909070;