15-78601445-G-A

Position:

• chr15-78601445-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000743.5(CHRNA3):​c.1197C>T​(p.Asp399=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,136 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (19 hom.)
• Consequence: CHRNA3 NM_000743.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.91

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-78601445-G-A is Benign according to our data. Variant chr15-78601445-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 722730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00338 (515/152244) while in subpopulation NFE AF= 0.00525 (357/68020). AF 95% confidence interval is 0.0048. There are 1 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA3	NM_000743.5	c.1197C>T	p.Asp399=	synonymous_variant	5/6	ENST00000326828.6	NP_000734.2
CHRNA3	NM_001166694.2	c.1197C>T	p.Asp399=	synonymous_variant	5/6		NP_001160166.1
CHRNA3	XM_006720382.4	c.996C>T	p.Asp332=	synonymous_variant	5/6		XP_006720445.1
CHRNA3	NR_046313.2	n.1399C>T		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA3	ENST00000326828.6	c.1197C>T	p.Asp399=	synonymous_variant	5/6	1	NM_000743.5	ENSP00000315602	P1
CHRNA3	ENST00000348639.7	c.1197C>T	p.Asp399=	synonymous_variant	5/6	1		ENSP00000267951
CHRNA3	ENST00000559658.5	c.1197C>T	p.Asp399=	synonymous_variant, NMD_transcript_variant	5/8	2		ENSP00000452896

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 515 AN: 152124 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00358 AC: 901 AN: 251376 Hom.: 3 AF XY: 0.00348 AC XY: 473 AN XY: 135864

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00799

Gnomad NFE exome AF: 0.00505

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00284 AC: 4159 AN: 1461892 Hom.: 19 Cov.: 31 AF XY: 0.00293 AC XY: 2129 AN XY: 727246

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00801

Gnomad4 NFE exome AF: 0.00291

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00338 AC: 515 AN: 152244 Hom.: 1 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74452

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00436 Hom.: 1

Bravo AF: 0.00229

EpiCase AF: 0.00420

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CHRNA3: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -

Smoking as a quantitative trait locus 3;C5231389:Urinary bladder, atony of Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.053
DANN	Benign	0.44

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: rs56403513; hg19: chr15-78893787;