rs4887067

Variant names:

• chr15-78594605-G-A
• rs4887067
• NM_000745.4:c.*1352G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000745.4(CHRNA5):​c.*1352G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,310 control chromosomes in the GnomAD database, including 5,800 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 0.24 (5793 hom., cov: 32)
  • Exomes 𝑓: 0.23 (7 hom.)
• Consequence: CHRNA5 NM_000745.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 18 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

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.*1352G>A		3_prime_UTR	Exon 6 of 6	NP_000736.2
	CHRNA5	NM_001395171.1		c.*1489G>A		3_prime_UTR	Exon 6 of 6	NP_001382100.1
	CHRNA5	NM_001395172.1		c.*1352G>A		3_prime_UTR	Exon 6 of 6	NP_001382101.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA5	ENST00000299565.9	TSL:1 MANE Select	c.*1352G>A		3_prime_UTR	Exon 6 of 6	ENSP00000299565.5	P30532
	CHRNA3	ENST00000348639.7	TSL:1	c.1390-1414C>T		intron	N/A	ENSP00000267951.4	P32297-3
	CHRNA3	ENST00000559002.5	TSL:1	n.194-1414C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36641 AN: 152026 Hom.: 5792 Cov.: 32

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.375

Gnomad EAS AF: 0.0324

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.276

GnomAD4 exome AF: 0.235 AC: 39 AN: 166 Hom.: 7 Cov.: 0 AF XY: 0.225 AC XY: 27 AN XY: 120

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.272 AC: 37 AN: 136

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.241 AC: 36643 AN: 152144 Hom.: 5793 Cov.: 32 AF XY: 0.238 AC XY: 17722 AN XY: 74356

African (AFR) AF: 0.0612 AC: 2540 AN: 41534

American (AMR) AF: 0.226 AC: 3458 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 1294 AN: 3454

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5178

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4820

European-Finnish (FIN) AF: 0.327 AC: 3464 AN: 10580

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23582 AN: 67976

Other (OTH) AF: 0.274 AC: 579 AN: 2114

Alfa AF: 0.273 Hom.: 864

Bravo AF: 0.225

Asia WGS AF: 0.115 AC: 403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.82
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs4887067; hg19: chr15-78886947;