Genetic Variant GRIA3:c.269-32471G>A (chrX-123220832-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000828.5(GRIA3):c.269-32471G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 23227 hom., 24569 hem., cov: 22)

Failed GnomAD Quality Control

Consequence

GRIA3
NM_000828.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.38

Publications

0 publications found

Variant links:

Genes affected

GRIA3 (HGNC:4573): (glutamate ionotropic receptor AMPA type subunit 3) Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)-sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties. [provided by RefSeq, Jul 2008]

GRIA3 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 94
Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability due to GRIA3 anomalies
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GRIA3 links:

ENSG00000307341 (HGNC:):

ENSG00000307341 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5 link	c.269-32471G>A		intron_variant	Intron 2 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 link	c.269-32471G>A		intron_variant	Intron 2 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2 link	c.269-32471G>A		intron_variant	Intron 2 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5 link	c.269-32471G>A		intron_variant	Intron 2 of 15	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes

AF:

0.754

AC:

83098

AN:

110190

Hom.:

23246

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.909

Gnomad AMR

AF:

0.748

Gnomad ASJ

AF:

0.881

Gnomad EAS

AF:

0.902

Gnomad SAS

AF:

0.785

Gnomad FIN

AF:

0.850

Gnomad MID

AF:

0.803

Gnomad NFE

AF:

0.877

Gnomad OTH

AF:

0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.754

AC:

83111

AN:

110247

Hom.:

23227

Cov.:

AF XY:

0.756

AC XY:

24569

AN XY:

32495

show subpopulations

African (AFR)

AF:

0.488

AC:

14786

AN:

30300

American (AMR)

AF:

0.748

AC:

7753

AN:

10361

Ashkenazi Jewish (ASJ)

AF:

0.881

AC:

2307

AN:

2619

East Asian (EAS)

AF:

0.902

AC:

3133

AN:

3473

South Asian (SAS)

AF:

0.781

AC:

1997

AN:

2556

European-Finnish (FIN)

AF:

0.850

AC:

4912

AN:

5779

Middle Eastern (MID)

AF:

0.785

AC:

168

AN:

214

European-Non Finnish (NFE)

AF:

0.878

AC:

46308

AN:

52772

Other (OTH)

AF:

0.756

AC:

1129

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

613

1226

1840

2453

3066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

706

1412

2118

2824

3530

<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:

0.822

Hom.:

94859

Bravo

AF:

0.737

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.053

(source)

DANN

Benign

0.75

PhyloP100

-1.4

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over