rs4950

Variant names:

• chr8-42697490-G-A
• rs4950
• NM_000749.5:c.-57G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-42697490-G-A
• chr8-42697490-G-C
• chr8-42697490-G-T

Variant summary

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

The NM_000749.5(CHRNB3):​c.-57G>A variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.266
• Publications: 64 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHRNB3	NM_000749.5	c.-57G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	ENST00000289957.3	NP_000740.1
CHRNB3	NM_000749.5	c.-57G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000289957.3	NP_000740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB3	ENST00000289957.3	c.-57G>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 6	1	NM_000749.5	ENSP00000289957.2
CHRNB3	ENST00000289957.3	c.-57G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_000749.5	ENSP00000289957.2

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

African (AFR) AF: 0.248 AC: 7663 AN: 30926

American (AMR) AF: 0.744 AC: 32875 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.708 AC: 17872 AN: 25244

East Asian (EAS) AF: 0.839 AC: 32555 AN: 38812

South Asian (SAS) AF: 0.699 AC: 57871 AN: 82756

European-Finnish (FIN) AF: 0.762 AC: 40339 AN: 52932

Middle Eastern (MID) AF: 0.670 AC: 3696 AN: 5520

European-Non Finnish (NFE) AF: 0.776 AC: 774823 AN: 998380

Other (OTH) AF: 0.727 AC: 40580 AN: 55810

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

African (AFR) AF: 0.264 AC: 10946 AN: 41446

American (AMR) AF: 0.707 AC: 10800 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2439 AN: 3466

East Asian (EAS) AF: 0.806 AC: 4165 AN: 5166

South Asian (SAS) AF: 0.711 AC: 3423 AN: 4812

European-Finnish (FIN) AF: 0.760 AC: 8034 AN: 10570

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.778 AC: 52878 AN: 67996

Other (OTH) AF: 0.658 AC: 1389 AN: 2112

Alfa AF: 0.713 Hom.: 106774

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
PhyloP100		0.27
PromoterAI		0.0058	Neutral
Mutation Taster		=300/0	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: rs4950; hg19: chr8-42552633; COSMIC: COSV51497205;