4-46928613-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000809.4(GABRA4):c.1277G>A(p.Arg426Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: GABRA4 NM_000809.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

Genes affected

GABRA4 (HGNC:4078): (gamma-aminobutyric acid type A receptor subunit alpha4) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 16 distinct subunits of GABA-A receptors have been identified. This gene encodes subunit alpha-4, which is involved in the etiology of autism and eventually increases autism risk through interaction with another subunit, gamma-aminobutyric acid receptor beta-1 (GABRB1). Alternatively spliced transcript variants encoding different isoforms have been found in this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04853204).
• BP6: Variant 4-46928613-C-T is Benign according to our data. Variant chr4-46928613-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2350758.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRA4	NM_000809.4	c.1277G>A	p.Arg426Gln	missense_variant	9/9	ENST00000264318.4
GABRA4	NM_001204266.2	c.1220G>A	p.Arg407Gln	missense_variant	9/9
GABRA4	NM_001204267.2	c.1067G>A	p.Arg356Gln	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRA4	ENST00000264318.4	c.1277G>A	p.Arg426Gln	missense_variant	9/9	1	NM_000809.4	P1
GABRA4	ENST00000508560.5	c.*1098G>A		3_prime_UTR_variant, NMD_transcript_variant	9/9	3
GABRA4	ENST00000511523.5	c.*945G>A		3_prime_UTR_variant, NMD_transcript_variant	8/8	3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251082 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135672

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727054

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74246

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	16
Dann	Benign	0.89
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.20
Sift	Benign	0.28	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.036
MVP		0.36
MPC		0.061
ClinPred		0.038	T
GERP RS		2.0
Varity_R		0.033
gMVP		0.20

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: rs369080252; hg19: chr4-46930630;