rs3787137

Variant names:

• chr20-63347748-G-A
• rs3787137
• NM_000744.7:c.1759-885C>T

Variant summary

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

The NM_000744.7(CHRNA4):​c.1759-885C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.426 in 152,104 control chromosomes in the GnomAD database, including 16,557 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 0.43 (16557 hom., cov: 33)
• Consequence: CHRNA4 NM_000744.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.773
• Publications: 13 publications found

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA4 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1759-885C>T		intron_variant	Intron 5 of 5	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.1231-885C>T		intron_variant	Intron 5 of 5		NP_001243502.1
CHRNA4	NR_046317.2	n.1968-885C>T		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1759-885C>T		intron_variant	Intron 5 of 5	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64754 AN: 151986 Hom.: 16549 Cov.: 33

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.517

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.389

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.434

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.426 AC: 64767 AN: 152104 Hom.: 16557 Cov.: 33 AF XY: 0.430 AC XY: 31949 AN XY: 74342

African (AFR) AF: 0.135 AC: 5590 AN: 41536

American (AMR) AF: 0.517 AC: 7912 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 1593 AN: 3468

East Asian (EAS) AF: 0.388 AC: 2003 AN: 5156

South Asian (SAS) AF: 0.437 AC: 2102 AN: 4814

European-Finnish (FIN) AF: 0.540 AC: 5717 AN: 10588

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.567 AC: 38504 AN: 67942

Other (OTH) AF: 0.437 AC: 922 AN: 2110

Alfa AF: 0.498 Hom.: 2594

Bravo AF: 0.409

Asia WGS AF: 0.399 AC: 1388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.97
PhyloP100		-0.77
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: rs3787137; hg19: chr20-61979100; COSMIC: COSV64720591; COSMIC: COSV64720591;