rs578776

Positions:

• chr15-78596058-G-A
• chr15-78596058-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.*546C>T		3_prime_UTR_variant	6/6	ENST00000326828.6	NP_000734.2
CHRNA3	XM_006720382.4	c.*546C>T		3_prime_UTR_variant	6/6		XP_006720445.1
CHRNA3	NM_001166694.2	c.1390-2867C>T		intron_variant			NP_001160166.1
CHRNA3	NR_046313.2	n.1784+482C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.*546C>T		3_prime_UTR_variant	6/6	1	NM_000743.5	ENSP00000315602	P1
CHRNA3	ENST00000348639.7	c.1390-2867C>T		intron_variant		1		ENSP00000267951
CHRNA3	ENST00000559002.5	n.193+482C>T		intron_variant, non_coding_transcript_variant		1
CHRNA3	ENST00000559658.5	c.*64+482C>T		intron_variant, NMD_transcript_variant		2		ENSP00000452896

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

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.592

Gnomad4 ASJ exome AF: 0.257

Gnomad4 EAS exome AF: 0.797

Gnomad4 SAS exome AF: 0.453

Gnomad4 FIN exome AF: 0.344

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.343

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

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.785

Gnomad4 SAS AF: 0.469

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.392

Alfa AF: 0.306 Hom.: 17525

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs578776; hg19: chr15-78888400;