chr15-78593235-T-G

Variant names:

• chr15-78593235-T-G
• rs1318987637
• NM_000745.4:c.1389T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000745.4(CHRNA5):​c.1389T>G​(p.Ile463Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,610,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHRNA5 NM_000745.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.126
• Publications: 0 publications found

Genes affected

CHRNA5 (HGNC:1959): (cholinergic receptor nicotinic alpha 5 subunit) The protein encoded by this gene is a nicotinic acetylcholine receptor subunit and a member of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. These receptors are thought to be heteropentamers composed of separate but similar subunits. Defects in this gene have been linked to susceptibility to lung cancer type 2 (LNCR2).[provided by RefSeq, Jun 2010]

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.087978214).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000745.4. 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
	CHRNA5	NM_000745.4	MANE Select	c.1389T>G	p.Ile463Met	missense	Exon 6 of 6	NP_000736.2
	CHRNA5	NM_001395172.1		c.735T>G	p.Ile245Met	missense	Exon 6 of 6	NP_001382101.1
	CHRNA5	NM_001395171.1		c.*119T>G		3_prime_UTR	Exon 6 of 6	NP_001382100.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.1389T>G	p.Ile463Met	missense	Exon 6 of 6	ENSP00000299565.5	P30532
	CHRNA3	ENST00000348639.7	TSL:1	c.1390-44A>C		intron	N/A	ENSP00000267951.4	P32297-3
	CHRNA3	ENST00000559002.5	TSL:1	n.194-44A>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458354 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725180

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 84988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5612

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110994

Other (OTH) AF: 0.00 AC: 0 AN: 60236

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	6.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.13
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.21
Sift	Uncertain	0.011	D
Sift4G	Benign	0.33	T
Polyphen		0.76	P
Vest4		0.14
MutPred		0.25		Gain of sheet (P = 0.0149)
MVP		0.83
MPC		0.39
ClinPred		0.21	T
GERP RS		2.9
Varity_R		0.071
gMVP		0.38
Mutation Taster		=84/16	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: rs1318987637; hg19: chr15-78885577;