Genetic Variant NM_000808.4:c.-117A>C (chrX-152451236-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000808.4(GABRA3):c.-117A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 21039 hom., 23265 hem., cov: 22)

Exomes 𝑓: 0.80 ( 18 hom. 67 hem. )

Failed GnomAD Quality Control

Consequence

GABRA3
NM_000808.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0520

Publications

5 publications found

Variant links:

Genes affected

GABRA3 (HGNC:4077): (gamma-aminobutyric acid type A receptor subunit alpha3) 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. [provided by RefSeq, Jul 2008]

GABRA3 Gene-Disease associations (from GenCC):

epilepsy, X-linked 2, with or without impaired intellectual development and dysmorphic features
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina

GABRA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant X-152451236-T-G is Benign according to our data. Variant chrX-152451236-T-G is described in ClinVar as Benign. ClinVar VariationId is 1241796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRA3	NM_000808.4 link	c.-117A>C		5_prime_UTR_variant	Exon 1 of 10	ENST00000370314.9	NP_000799.1	P34903
GABRA3	XM_006724811.4 link	c.-117A>C		5_prime_UTR_variant	Exon 1 of 9		XP_006724874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRA3	ENST00000370314.9 link	c.-117A>C		5_prime_UTR_variant	Exon 1 of 10	1	NM_000808.4	ENSP00000359337.4		P34903

Frequencies

GnomAD3 genomes

AF:

0.729

AC:

79544

AN:

109076

Hom.:

21046

Cov.:

show subpopulations

Gnomad AFR

AF:

0.554

Gnomad AMI

AF:

0.907

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.806

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.659

Gnomad FIN

AF:

0.810

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.822

Gnomad OTH

AF:

0.729

GnomAD4 exome

AF:

0.804

AC:

115

AN:

143

Hom.:

Cov.:

AF XY:

0.848

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.333

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.800

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.836

AC:

102

AN:

122

Other (OTH)

AF:

0.400

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.729

AC:

79544

AN:

109125

Hom.:

21039

Cov.:

AF XY:

0.727

AC XY:

23265

AN XY:

31997

show subpopulations

African (AFR)

AF:

0.554

AC:

16320

AN:

29470

American (AMR)

AF:

0.762

AC:

7931

AN:

10409

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

2108

AN:

2617

East Asian (EAS)

AF:

0.534

AC:

1812

AN:

3395

South Asian (SAS)

AF:

0.659

AC:

1641

AN:

2491

European-Finnish (FIN)

AF:

0.810

AC:

4715

AN:

5824

Middle Eastern (MID)

AF:

0.741

AC:

157

AN:

212

European-Non Finnish (NFE)

AF:

0.822

AC:

43181

AN:

52548

Other (OTH)

AF:

0.719

AC:

1067

AN:

1484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

732

1463

2195

2926

3658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

672

1344

2016

2688

3360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.761

Hom.:

11689

Bravo

AF:

0.711

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.91

(source)

DANN

Benign

0.82

PhyloP100

-0.052

PromoterAI

0.068

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over