NM_000744.7:c.1460G>A

Variant names:

• chr20-63349951-C-T
• rs121912280
• NM_000744.7:c.1460G>A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000744.7(CHRNA4):​c.1460G>A​(p.Arg487Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,576,496 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (3 hom.)
• Consequence: CHRNA4 NM_000744.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7 O:1
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011544973).
• BP6: Variant 20-63349951-C-T is Benign according to our data. Variant chr20-63349951-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98318.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=2, not_provided=1}. Variant chr20-63349951-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7	c.1460G>A	p.Arg487Gln	missense_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2	c.932G>A	p.Arg311Gln	missense_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2	n.1669G>A		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9	c.1460G>A	p.Arg487Gln	missense_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000649 AC: 126 AN: 194062 Hom.: 1 AF XY: 0.000606 AC XY: 64 AN XY: 105690

Gnomad AFR exome AF: 0.00465

Gnomad AMR exome AF: 0.000389

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.0000679

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.000813

GnomAD4 exome AF: 0.000345 AC: 492 AN: 1424182 Hom.: 3 Cov.: 83 AF XY: 0.000358 AC XY: 252 AN XY: 704326

Gnomad4 AFR exome AF: 0.00470

Gnomad4 AMR exome AF: 0.000606

Gnomad4 ASJ exome AF: 0.000475

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.000449

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.000886

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74488

Gnomad4 AFR AF: 0.00411

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.00173

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00277 AC: 12

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000596 AC: 71

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHRNA4: BS1, BS2 -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 08, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19628475, 21107856, 24385388, 22873564, 29422393) -

Autosomal dominant nocturnal frontal lobe epilepsy 1 Uncertain:1

Oct 26, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHRNA4 NM_000744.6 exon 5 p.Arg487Gln (c.1460G>A): This variant has been reported in the literature in 1 individual with Sporadic Amyotrophic Lateral Sclerosis (SALS) (Sabatelli 2009 PMID:19628475). This variant is present in 0.4% (85/1944) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912280). This variant Glutamine (Gln) is present in >5 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Autosomal dominant nocturnal frontal lobe epilepsy 1;C1861063:Tobacco addiction, susceptibility to Uncertain:1

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHRNA4 NM_000744 exon 5 p.Arg487Gln (c.1460G>A): This variant has been reported in the literature in 1 individual with Sporadic Amyotrophic Lateral Sclerosis (SALS) (Sabatelli 2009 PMID:19628475). This variant is present in 0.4% (85/1944) of African alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121912280). This variant Glutamine (Gln) is present in >5 species including mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified Benign:1

Oct 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Nov 26, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Tobacco use disorder Other:1

-

Psychiatry Genetics Yale University

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.79	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.037	D;.
Sift4G	Benign	0.31	T;T
Polyphen		0.45	B;.
Vest4		0.23
MVP		0.77
MPC		0.48
ClinPred		0.0044	T
GERP RS		2.9
Varity_R		0.097
gMVP		0.30

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: rs121912280; hg19: chr20-61981303;