rs4954

Variant names:

• chr8-42732653-G-A
• rs4954
• NM_000749.5:c.1242+104G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-42732653-G-A
• chr8-42732653-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.1242+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.931 in 1,053,734 control chromosomes in the GnomAD database, including 458,169 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 0.90 (61451 hom., cov: 33)
  • Exomes 𝑓: 0.94 (396718 hom.)
• Consequence: CHRNB3 NM_000749.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.957
• Publications: 15 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000749.5. 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
	CHRNB3	NM_000749.5	MANE Select	c.1242+104G>A		intron	N/A	NP_000740.1	Q05901
	CHRNB3	NM_001347717.2		c.1020+104G>A		intron	N/A	NP_001334646.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB3	ENST00000289957.3	TSL:1 MANE Select	c.1242+104G>A		intron	N/A	ENSP00000289957.2	Q05901

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136220 AN: 152084 Hom.: 61416 Cov.: 33

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.958

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.896

GnomAD4 exome AF: 0.937 AC: 845117 AN: 901532 Hom.: 396718 AF XY: 0.937 AC XY: 423330 AN XY: 451726

African (AFR) AF: 0.786 AC: 16467 AN: 20946

American (AMR) AF: 0.865 AC: 15214 AN: 17598

Ashkenazi Jewish (ASJ) AF: 0.912 AC: 15063 AN: 16518

East Asian (EAS) AF: 0.893 AC: 30532 AN: 34206

South Asian (SAS) AF: 0.913 AC: 45743 AN: 50106

European-Finnish (FIN) AF: 0.934 AC: 31461 AN: 33698

Middle Eastern (MID) AF: 0.909 AC: 2844 AN: 3128

European-Non Finnish (NFE) AF: 0.950 AC: 650600 AN: 684974

Other (OTH) AF: 0.922 AC: 37193 AN: 40358

GnomAD4 genome AF: 0.896 AC: 136302 AN: 152202 Hom.: 61451 Cov.: 33 AF XY: 0.895 AC XY: 66618 AN XY: 74418

African (AFR) AF: 0.798 AC: 33072 AN: 41468

American (AMR) AF: 0.883 AC: 13499 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3170 AN: 3470

East Asian (EAS) AF: 0.858 AC: 4449 AN: 5184

South Asian (SAS) AF: 0.909 AC: 4388 AN: 4828

European-Finnish (FIN) AF: 0.939 AC: 9963 AN: 10614

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.951 AC: 64726 AN: 68040

Other (OTH) AF: 0.894 AC: 1888 AN: 2112

Alfa AF: 0.931 Hom.: 13402

Bravo AF: 0.884

Asia WGS AF: 0.846 AC: 2941 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.35
DANN	Benign	0.77
PhyloP100		-0.96
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: rs4954; hg19: chr8-42587796; COSMIC: COSV51493958;