15-78596058-G-A

Variant names:

• chr15-78596058-G-A
• rs578776
• NM_000743.5:c.*546C>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.*546C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 980,552 control chromosomes in the GnomAD database, including 51,406 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 (13877 hom., cov: 32)
  • Exomes 𝑓: 0.29 (37529 hom.)
• Consequence: CHRNA3 NM_000743.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.269
• Publications: 180 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=-0.88).
• 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
CHRNA3	NM_000743.5	c.*546C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.*546C>T		3_prime_UTR_variant	Exon 6 of 6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-2867C>T		intron_variant	Intron 5 of 5		NP_001160166.1
CHRNA3	NR_046313.2	n.1784+482C>T		intron_variant	Intron 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.*546C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.1390-2867C>T		intron_variant	Intron 5 of 5	1		ENSP00000267951.4
CHRNA3	ENST00000559002.5	n.193+482C>T		intron_variant	Intron 1 of 1	1
CHRNA3	ENST00000559658.5	n.*64+482C>T		intron_variant	Intron 6 of 7	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60651 AN: 151952 Hom.: 13846 Cov.: 32

Gnomad AFR AF: 0.539

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.293 AC: 242706 AN: 828482 Hom.: 37529 Cov.: 21 AF XY: 0.292 AC XY: 111870 AN XY: 382700

African (AFR) AF: 0.564 AC: 8820 AN: 15646

American (AMR) AF: 0.592 AC: 581 AN: 982

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 1315 AN: 5126

East Asian (EAS) AF: 0.797 AC: 2863 AN: 3594

South Asian (SAS) AF: 0.453 AC: 7401 AN: 16352

European-Finnish (FIN) AF: 0.344 AC: 95 AN: 276

Middle Eastern (MID) AF: 0.347 AC: 556 AN: 1600

European-Non Finnish (NFE) AF: 0.279 AC: 211765 AN: 757790

Other (OTH) AF: 0.343 AC: 9310 AN: 27116

GnomAD4 genome AF: 0.399 AC: 60734 AN: 152070 Hom.: 13877 Cov.: 32 AF XY: 0.406 AC XY: 30156 AN XY: 74350

African (AFR) AF: 0.538 AC: 22328 AN: 41464

American (AMR) AF: 0.526 AC: 8049 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 925 AN: 3468

East Asian (EAS) AF: 0.785 AC: 4064 AN: 5174

South Asian (SAS) AF: 0.469 AC: 2264 AN: 4824

European-Finnish (FIN) AF: 0.321 AC: 3392 AN: 10576

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18619 AN: 67950

Other (OTH) AF: 0.392 AC: 829 AN: 2114

Alfa AF: 0.324 Hom.: 41970

Bravo AF: 0.422

Asia WGS AF: 0.622 AC: 2161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.66
DANN	Benign	0.53
PhyloP100		-0.27
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: rs578776; hg19: chr15-78888400;