rs8192479

Variant names:

• chr15-78617056-C-T
• rs8192479
• NM_000743.5:c.345G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_000743.5(CHRNA3):​c.345G>A​(p.Lys115Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,480 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.017 (255 hom.)
• Consequence: CHRNA3 NM_000743.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.957
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 15-78617056-C-T is Benign according to our data. Variant chr15-78617056-C-T is described in ClinVar as Benign. ClinVar VariationId is 2123513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.957 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1974/152340) while in subpopulation NFE AF = 0.0209 (1420/68040). AF 95% confidence interval is 0.02. There are 19 homozygotes in GnomAd4. There are 897 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.345G>A	p.Lys115Lys	synonymous_variant	Exon 4 of 6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.345G>A	p.Lys115Lys	synonymous_variant	Exon 4 of 6		NP_001160166.1
CHRNA3	XM_006720382.4	c.144G>A	p.Lys48Lys	synonymous_variant	Exon 4 of 6		XP_006720445.1
CHRNA3	NR_046313.2	n.547G>A		non_coding_transcript_exon_variant	Exon 4 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.345G>A	p.Lys115Lys	synonymous_variant	Exon 4 of 6	1	NM_000743.5	ENSP00000315602.5
CHRNA3	ENST00000348639.7	c.345G>A	p.Lys115Lys	synonymous_variant	Exon 4 of 6	1		ENSP00000267951.4
CHRNA3	ENST00000559658.5	n.345G>A		non_coding_transcript_exon_variant	Exon 4 of 8	2		ENSP00000452896.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 152222 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00321

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0129 AC: 3225 AN: 250890 AF XY: 0.0130

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00905

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0281

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0173 AC: 25349 AN: 1461140 Hom.: 255 Cov.: 30 AF XY: 0.0170 AC XY: 12355 AN XY: 726910

African (AFR) AF: 0.00281 AC: 94 AN: 33478

American (AMR) AF: 0.00396 AC: 177 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86194

European-Finnish (FIN) AF: 0.0276 AC: 1470 AN: 53288

Middle Eastern (MID) AF: 0.00701 AC: 40 AN: 5710

European-Non Finnish (NFE) AF: 0.0200 AC: 22179 AN: 1111568

Other (OTH) AF: 0.0164 AC: 990 AN: 60378

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 152340 Hom.: 19 Cov.: 32 AF XY: 0.0120 AC XY: 897 AN XY: 74488

African (AFR) AF: 0.00320 AC: 133 AN: 41574

American (AMR) AF: 0.00693 AC: 106 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00165 AC: 8 AN: 4834

European-Finnish (FIN) AF: 0.0241 AC: 256 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0209 AC: 1420 AN: 68040

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0162 Hom.: 37

Bravo AF: 0.0114

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0185

EpiControl AF: 0.0193

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		0.96
Mutation Taster		=99/1	polymorphism

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: rs8192479; hg19: chr15-78909398;