15-78593885-A-G

Variant names:

• chr15-78593885-A-G
• rs564585
• NM_000745.4:c.*632A>G

Variant summary

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

The NM_000745.4(CHRNA5):​c.*632A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,874 control chromosomes in the GnomAD database, including 13,814 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 0.40 (13814 hom., cov: 31)
  • Exomes 𝑓: 0.19 (0 hom.)
• Consequence: CHRNA5 NM_000745.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA5	NM_000745.4	c.*632A>G		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.*632A>G		3_prime_UTR_variant	Exon 6 of 6	1	NM_000745.4	ENSP00000299565.5

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60490 AN: 151724 Hom.: 13782 Cov.: 31

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.387

GnomAD4 exome AF: 0.188 AC: 6 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.208 AC XY: 5 AN XY: 24

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.179 AC: 5 AN: 28

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.399 AC: 60574 AN: 151842 Hom.: 13814 Cov.: 31 AF XY: 0.405 AC XY: 30058 AN XY: 74198

African (AFR) AF: 0.538 AC: 22231 AN: 41358

American (AMR) AF: 0.526 AC: 8015 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 966 AN: 3468

East Asian (EAS) AF: 0.786 AC: 4041 AN: 5144

South Asian (SAS) AF: 0.470 AC: 2259 AN: 4810

European-Finnish (FIN) AF: 0.321 AC: 3376 AN: 10532

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.274 AC: 18595 AN: 67972

Other (OTH) AF: 0.393 AC: 829 AN: 2108

Alfa AF: 0.345 Hom.: 1266

Bravo AF: 0.422

Asia WGS AF: 0.624 AC: 2169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.2
DANN	Benign	0.31
PhyloP100		1.1
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: rs564585; hg19: chr15-78886227;