Genetic Variant GABRQ:p.Ile478Phe (chrX-152652814-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_018558.4(GABRQ):c.1432A>T(p.Ile478Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,207,414 control chromosomes in the GnomAD database, including 79,082 homozygotes. There are 175,185 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.48 ( 9130 hom., 15686 hem., cov: 23)

Exomes 𝑓: 0.43 ( 69952 hom. 159499 hem. )

Consequence

GABRQ
NM_018558.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.649

Publications

34 publications found

Variant links:

Genes affected

GABRQ (HGNC:14454): (gamma-aminobutyric acid type A receptor subunit theta) The gamma-aminobutyric acid (GABA) A receptor is a multisubunit chloride channel that mediates the fastest inhibitory synaptic transmission in the central nervous system. This gene encodes the theta subunit of the GABA A receptor. The gene is mapped to chromosome Xq28 in a cluster of genes including those that encode the alpha 3 and epsilon subunits of the GABA A receptor. [provided by RefSeq, Jul 2017]

GABRQ links:

MAGEA3-DT (HGNC:56247): (MAGEA3 divergent transcript)

MAGEA3-DT links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052278936).

BP6

Variant X-152652814-A-T is Benign according to our data. Variant chrX-152652814-A-T is described in ClinVar as Benign. ClinVar VariationId is 769197.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRQ	NM_018558.4 link	c.1432A>T	p.Ile478Phe	missense_variant	Exon 9 of 9	ENST00000598523.3	NP_061028.3	Q9UN88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRQ	ENST00000598523.3 link	c.1432A>T	p.Ile478Phe	missense_variant	Exon 9 of 9	1	NM_018558.4	ENSP00000469332.1		Q9UN88
MAGEA3-DT	ENST00000671457.1 link	n.130-13020T>A		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.476

AC:

52522

AN:

110422

Hom.:

9134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.605

Gnomad AMI

AF:

0.394

Gnomad AMR

AF:

0.348

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.668

Gnomad SAS

AF:

0.542

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.397

Gnomad NFE

AF:

0.421

Gnomad OTH

AF:

0.445

GnomAD4 exome

AF:

0.434

AC:

475617

AN:

1096943

Hom.:

69952

Cov.:

AF XY:

0.440

AC XY:

159499

AN XY:

362513

show subpopulations

African (AFR)

AF:

0.614

AC:

15942

AN:

25963

American (AMR)

AF:

0.307

AC:

10801

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.370

AC:

7167

AN:

19382

East Asian (EAS)

AF:

0.681

AC:

20560

AN:

30204

South Asian (SAS)

AF:

0.552

AC:

29863

AN:

54138

European-Finnish (FIN)

AF:

0.455

AC:

18450

AN:

40521

Middle Eastern (MID)

AF:

0.382

AC:

1574

AN:

4120

European-Non Finnish (NFE)

AF:

0.416

AC:

350294

AN:

841396

Other (OTH)

AF:

0.455

AC:

20966

AN:

46033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

11582

23163

34745

46326

57908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11942

23884

35826

47768

59710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.476

AC:

52558

AN:

110471

Hom.:

9130

Cov.:

AF XY:

0.477

AC XY:

15686

AN XY:

32913

show subpopulations

African (AFR)

AF:

0.605

AC:

18157

AN:

29993

American (AMR)

AF:

0.348

AC:

3684

AN:

10590

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

965

AN:

2633

East Asian (EAS)

AF:

0.667

AC:

2294

AN:

3437

South Asian (SAS)

AF:

0.541

AC:

1406

AN:

2601

European-Finnish (FIN)

AF:

0.464

AC:

2791

AN:

6020

Middle Eastern (MID)

AF:

0.389

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.421

AC:

22241

AN:

52806

Other (OTH)

AF:

0.447

AC:

673

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

987

1974

2962

3949

4936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.574

Hom.:

5585

Bravo

AF:

0.472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.52

(source)

MetaRNN

Benign

0.0052

PhyloP100

-0.65

Sift4G

Uncertain

0.027

Vest4

0.071

gMVP

0.16

Splicing

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over