rs3743072

Variant names:

• chr15-78629420-G-A
• rs3743072
• NM_000750.5:c.885C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000750.5(CHRNB4):​c.885C>T​(p.Ile295Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,072 control chromosomes in the GnomAD database, including 571 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 0.035 (236 hom., cov: 31)
  • Exomes 𝑓: 0.010 (335 hom.)
• Consequence: CHRNB4 NM_000750.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187

Genes affected

CHRNB4 (HGNC:1964): (cholinergic receptor nicotinic beta 4 subunit) This gene is found within a conserved gene cluster and encodes one of the beta subunits of the nicotinic acetylcholine receptor (nAChRs) superfamily which form ligand-gated ion channels with a central pore that forms a cation channel. Neuronal nAChRs are pentameric structures that can be either homomeric or heteromeric, with heteromeric structures containing both alpha and beta subunits. Each subunit contains an extracellular amino terminus and four transmembrane domains. Nicotine is one of the agonists that binds to the receptor. Variants in this gene have been associated with nicotine dependence and lung cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-0.187 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.885C>T	p.Ile295Ile	synonymous_variant	Exon 5 of 6	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.885C>T	p.Ile295Ile	synonymous_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.359+1656C>T		intron_variant	Intron 4 of 4	1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.*941C>T		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000457404.1
CHRNB4	ENST00000559849.5	n.*941C>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000457404.1

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5335 AN: 152090 Hom.: 235 Cov.: 31

Gnomad AFR AF: 0.0983

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00609

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0184 AC: 4625 AN: 251386 Hom.: 162 AF XY: 0.0164 AC XY: 2229 AN XY: 135864

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0783

Gnomad SAS exome AF: 0.00728

Gnomad FIN exome AF: 0.00491

Gnomad NFE exome AF: 0.00624

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0101 AC: 14710 AN: 1461864 Hom.: 335 Cov.: 31 AF XY: 0.00968 AC XY: 7040 AN XY: 727232

Gnomad4 AFR exome AF: 0.0967

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0720

Gnomad4 SAS exome AF: 0.00709

Gnomad4 FIN exome AF: 0.00453

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0352 AC: 5353 AN: 152208 Hom.: 236 Cov.: 31 AF XY: 0.0354 AC XY: 2634 AN XY: 74424

Gnomad4 AFR AF: 0.0985

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0836

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00609

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0190 Hom.: 41

Bravo AF: 0.0389

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.66
DANN	Benign	0.82

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: rs3743072; hg19: chr15-78921762; COSMIC: COSV55715239; COSMIC: COSV55715239;