rs4950

chr8-42697490-G-Achr8-42697490-G-Cchr8-42697490-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000749.5(CHRNB3):c.-57G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.742 in 1,486,606 control chromosomes in the GnomAD database, including 419,730 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 0.62 (33682 hom., cov: 31)
  • Exomes 𝑓: 0.76 (386048 hom.)
• Consequence: CHRNB3 NM_000749.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266

Genes affected

CHRNB3 (HGNC:1963): (cholinergic receptor nicotinic beta 3 subunit) The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are (hetero)pentamers composed of homologous subunits. The subunits that make up the muscle and neuronal forms of nAChRs are encoded by separate genes and have different primary structure. There are several subtypes of neuronal nAChRs that vary based on which homologous subunits are arranged around the central channel. They are classified as alpha-subunits if, like muscle alpha-1 (MIM 100690), they have a pair of adjacent cysteines as part of the presumed acetylcholine binding site. Subunits lacking these cysteine residues are classified as beta-subunits (Groot Kormelink and Luyten, 1997 [PubMed 9009220]). Elliott et al. (1996) [PubMed 8906617] stated that the proposed structure for each subunit is a conserved N-terminal extracellular domain followed by 3 conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region.[supplied by OMIM, Apr 2010]

LOC124900250 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB3	NM_000749.5	c.-57G>A		5_prime_UTR_variant	1/6	ENST00000289957.3
LOC124900250	XR_001745887.2	n.91C>T		non_coding_transcript_exon_variant	2/3
CHRNB3	NM_001347717.2	c.-412G>A		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB3	ENST00000289957.3	c.-57G>A		5_prime_UTR_variant	1/6	1	NM_000749.5	P1
CHRNB3	ENST00000534391.1	c.-412G>A		5_prime_UTR_variant	1/4	3
CHRNB3	ENST00000531610.5	n.115G>A		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94994 AN: 151918 Hom.: 33675 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.760

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.656

GnomAD4 exome AF: 0.756 AC: 1008274 AN: 1334568 Hom.: 386048 Cov.: 18 AF XY: 0.754 AC XY: 504517 AN XY: 668712

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.744

Gnomad4 ASJ exome AF: 0.708

Gnomad4 EAS exome AF: 0.839

Gnomad4 SAS exome AF: 0.699

Gnomad4 FIN exome AF: 0.762

Gnomad4 NFE exome AF: 0.776

Gnomad4 OTH exome AF: 0.727

GnomAD4 genome AF: 0.625 AC: 95020 AN: 152038 Hom.: 33682 Cov.: 31 AF XY: 0.631 AC XY: 46897 AN XY: 74336

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.707

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.760

Gnomad4 NFE AF: 0.778

Gnomad4 OTH AF: 0.658

Alfa AF: 0.739 Hom.: 42171

Bravo AF: 0.604

Asia WGS AF: 0.705 AC: 2449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.61
Dann	Benign	0.57

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: rs4950; hg19: chr8-42552633; COSMIC: COSV51497205;