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GeneBe

4-46965099-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_000809.4(GABRA4):c.1005C>T(p.Ile335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000558 in 1,612,070 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00053 ( 10 hom. )

Consequence

GABRA4
NM_000809.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.34
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.33).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-46965099-G-A is Benign according to our data. Variant chr4-46965099-G-A is described in ClinVar as [Benign]. Clinvar id is 724381.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.34 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 124 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GABRA4NM_000809.4 linkuse as main transcriptc.1005C>T p.Ile335= synonymous_variant 8/9 ENST00000264318.4
GABRA4NM_001204266.2 linkuse as main transcriptc.948C>T p.Ile316= synonymous_variant 8/9
GABRA4NM_001204267.2 linkuse as main transcriptc.795C>T p.Ile265= synonymous_variant 7/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GABRA4ENST00000264318.4 linkuse as main transcriptc.1005C>T p.Ile335= synonymous_variant 8/91 NM_000809.4 P1
GABRA4ENST00000508560.5 linkuse as main transcriptc.*826C>T 3_prime_UTR_variant, NMD_transcript_variant 8/93
GABRA4ENST00000511523.5 linkuse as main transcriptc.*673C>T 3_prime_UTR_variant, NMD_transcript_variant 7/83

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000817
AC:
124
AN:
151688
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000218
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000263
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00273
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00755
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000192
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00113
AC:
283
AN:
250232
Hom.:
4
AF XY:
0.00111
AC XY:
150
AN XY:
135244
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.000610
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00333
Gnomad SAS exome
AF:
0.000850
Gnomad FIN exome
AF:
0.00633
Gnomad NFE exome
AF:
0.000212
Gnomad OTH exome
AF:
0.00213
GnomAD4 exome
AF:
0.000531
AC:
776
AN:
1460264
Hom.:
10
Cov.:
31
AF XY:
0.000540
AC XY:
392
AN XY:
726448
show subpopulations
Gnomad4 AFR exome
AF:
0.0000600
Gnomad4 AMR exome
AF:
0.000539
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00588
Gnomad4 SAS exome
AF:
0.000731
Gnomad4 FIN exome
AF:
0.00534
Gnomad4 NFE exome
AF:
0.000108
Gnomad4 OTH exome
AF:
0.000796
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000817
AC:
124
AN:
151806
Hom.:
0
Cov.:
33
AF XY:
0.00121
AC XY:
90
AN XY:
74166
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000263
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00274
Gnomad4 SAS
AF:
0.000830
Gnomad4 FIN
AF:
0.00755
Gnomad4 NFE
AF:
0.000192
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000259
Hom.:
0
Bravo
AF:
0.000264
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJul 20, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.33
Cadd
Benign
8.7
Dann
Benign
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs187564813; hg19: chr4-46967116; COSMIC: COSV51935715; API