NM_000744.7:c.1417A>G

Variant names:

• chr20-63349994-T-C
• rs1555837484
• NM_000744.7:c.1417A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000744.7(CHRNA4):​c.1417A>G​(p.Ser473Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S473N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.387
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19566777).
• BP6: Variant 20-63349994-T-C is Benign according to our data. Variant chr20-63349994-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 477002.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	NM_000744.7	MANE Select	c.1417A>G	p.Ser473Gly	missense	Exon 5 of 6	NP_000735.1
	CHRNA4	NM_001256573.2		c.889A>G	p.Ser297Gly	missense	Exon 5 of 6	NP_001243502.1
	CHRNA4	NR_046317.2		n.1626A>G		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1417A>G	p.Ser473Gly	missense	Exon 5 of 6	ENSP00000359285.4
	CHRNA4	ENST00000463705.5	TSL:1	n.2065A>G		non_coding_transcript_exon	Exon 4 of 5
	CHRNA4	ENST00000467563.3	TSL:1	n.1487A>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397456 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 688586

African (AFR) AF: 0.00 AC: 0 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 36696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23840

East Asian (EAS) AF: 0.00 AC: 0 AN: 37378

South Asian (SAS) AF: 0.00 AC: 0 AN: 77916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5464

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078728

Other (OTH) AF: 0.00 AC: 0 AN: 57650

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Oct 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	10
DANN	Benign	0.88
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.39
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.33		Gain of catalytic residue at S473 (P = 0.025)
MVP		0.85
MPC		0.37
ClinPred		0.18	T
GERP RS		-0.54
Varity_R		0.053
gMVP		0.24
Mutation Taster		=85/15	polymorphism

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: rs1555837484; hg19: chr20-61981346;