15-78616885-T-A

Variant names:

• chr15-78616885-T-A
• rs3743076
• NM_000743.5:c.377+139A>T

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+139A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 604,794 control chromosomes in the GnomAD database, including 1,405 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 0.028 (227 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1178 hom.)
• Consequence: CHRNA3 NM_000743.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.990
• Publications: 6 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.377+139A>T		intron_variant	Intron 4 of 5	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.377+139A>T		intron_variant	Intron 4 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.579+139A>T		intron_variant	Intron 4 of 7
CHRNA3	XM_006720382.4	c.176+139A>T		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+139A>T		intron_variant	Intron 4 of 5	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.377+139A>T		intron_variant	Intron 4 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559658.5	n.377+139A>T		intron_variant	Intron 4 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4287 AN: 152156 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.0236 AC: 10664 AN: 452520 Hom.: 1178 AF XY: 0.0221 AC XY: 5264 AN XY: 238398

African (AFR) AF: 0.0635 AC: 796 AN: 12544

American (AMR) AF: 0.00542 AC: 100 AN: 18456

Ashkenazi Jewish (ASJ) AF: 0.0203 AC: 278 AN: 13662

East Asian (EAS) AF: 0.268 AC: 8302 AN: 31034

South Asian (SAS) AF: 0.00763 AC: 339 AN: 44428

European-Finnish (FIN) AF: 0.000262 AC: 8 AN: 30538

Middle Eastern (MID) AF: 0.00813 AC: 16 AN: 1968

European-Non Finnish (NFE) AF: 0.000924 AC: 253 AN: 273830

Other (OTH) AF: 0.0219 AC: 572 AN: 26060

GnomAD4 genome AF: 0.0283 AC: 4302 AN: 152274 Hom.: 227 Cov.: 32 AF XY: 0.0288 AC XY: 2141 AN XY: 74452

African (AFR) AF: 0.0643 AC: 2672 AN: 41560

American (AMR) AF: 0.00797 AC: 122 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1276 AN: 5160

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68014

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.000380 Hom.: 0

Bravo AF: 0.0321

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.63
PhyloP100		-0.99
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3743076; hg19: chr15-78909227;