rs615470

Variant names:

• chr15-78593646-T-C
• rs615470
• NM_000745.4:c.*393T>C

Variant summary

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

The NM_000745.4(CHRNA5):​c.*393T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 156,536 control chromosomes in the GnomAD database, including 32,830 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 0.64 (31870 hom., cov: 33)
  • Exomes 𝑓: 0.66 (960 hom.)
• Consequence: CHRNA5 NM_000745.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527
• Publications: 45 publications found

Genes affected

CHRNA5 (HGNC:1959): (cholinergic receptor nicotinic alpha 5 subunit) The protein encoded by this gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2 (LNCR2).[provided by RefSeq, Jun 2010]

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=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA5	NM_000745.4	c.*393T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000299565.9	NP_000736.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA5	ENST00000299565.9	c.*393T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_000745.4	ENSP00000299565.5

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97904 AN: 151946 Hom.: 31834 Cov.: 33

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.757

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.697

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.669

GnomAD4 exome AF: 0.659 AC: 2948 AN: 4474 Hom.: 960 Cov.: 0 AF XY: 0.657 AC XY: 1567 AN XY: 2386

African (AFR) AF: 0.566 AC: 43 AN: 76

American (AMR) AF: 0.772 AC: 366 AN: 474

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 54 AN: 80

East Asian (EAS) AF: 0.845 AC: 120 AN: 142

South Asian (SAS) AF: 0.689 AC: 175 AN: 254

European-Finnish (FIN) AF: 0.679 AC: 72 AN: 106

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.635 AC: 1999 AN: 3150

Other (OTH) AF: 0.629 AC: 117 AN: 186

GnomAD4 genome AF: 0.644 AC: 97989 AN: 152062 Hom.: 31870 Cov.: 33 AF XY: 0.647 AC XY: 48101 AN XY: 74306

African (AFR) AF: 0.599 AC: 24832 AN: 41474

American (AMR) AF: 0.757 AC: 11564 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2270 AN: 3470

East Asian (EAS) AF: 0.819 AC: 4250 AN: 5188

South Asian (SAS) AF: 0.699 AC: 3367 AN: 4818

European-Finnish (FIN) AF: 0.649 AC: 6844 AN: 10540

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42687 AN: 67990

Other (OTH) AF: 0.673 AC: 1418 AN: 2108

Alfa AF: 0.636 Hom.: 77095

Bravo AF: 0.650

Asia WGS AF: 0.743 AC: 2584 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.9
DANN	Benign	0.90
PhyloP100		0.53
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: rs615470; hg19: chr15-78885988;