chr15-78596660-T-G

Variant names:

• chr15-78596660-T-G
• rs1289200750
• NM_000743.5:c.1462A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000743.5(CHRNA3):​c.1462A>C​(p.Ile488Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHRNA3 NM_000743.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000743.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA3	NM_000743.5	MANE Select	c.1462A>C	p.Ile488Leu	missense	Exon 6 of 6	NP_000734.2
	CHRNA3	NM_001166694.2		c.1390-3469A>C		intron	N/A	NP_001160166.1	P32297-3
	CHRNA3	NR_046313.2		n.1664A>C		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA3	ENST00000326828.6	TSL:1 MANE Select	c.1462A>C	p.Ile488Leu	missense	Exon 6 of 6	ENSP00000315602.5	P32297-2
	CHRNA3	ENST00000348639.7	TSL:1	c.1390-3469A>C		intron	N/A	ENSP00000267951.4	P32297-3
	CHRNA3	ENST00000559002.5	TSL:1	n.73A>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460940 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726832

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	SMOKING AS A QUANTITATIVE TRAIT LOCUS 3;C5231389:Urinary bladder, atony of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.54
Sift	Benign	0.50	T
Sift4G	Benign	0.54	T
Polyphen		0.37	B
Vest4		0.67
MutPred		0.62		Gain of catalytic residue at I488 (P = 0.0759)
MVP		0.78
MPC		0.90
ClinPred		0.83	D
GERP RS		5.1
Varity_R		0.13
gMVP		0.42
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1289200750; hg19: chr15-78889002;