dbSNP rs983007: GRIA3:c.269-11554A>C (chrX-123241749-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000828.5(GRIA3):c.269-11554A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 109,329 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 0.000018 ( 0 hom., 0 hem., cov: 22)

Consequence

GRIA3
NM_000828.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.457

Publications

3 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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5 link	c.269-11554A>C		intron_variant	Intron 2 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 link	c.269-11554A>C		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.269-11554A>C		intron_variant	Intron 2 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5 link	c.269-11554A>C		intron_variant	Intron 2 of 15	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes

AF:

0.0000183

AC:

AN:

109329

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000190

Gnomad OTH

AF:

0.00

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

GnomAD4 genome

AF:

0.0000183

AC:

AN:

109329

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31635

show subpopulations

African (AFR)

AF:

0.0000333

AC:

AN:

30064

American (AMR)

AF:

0.00

AC:

AN:

10143

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2610

East Asian (EAS)

AF:

0.00

AC:

AN:

3430

South Asian (SAS)

AF:

0.00

AC:

AN:

2513

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5689

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

52506

Other (OTH)

AF:

0.00

AC:

AN:

1467

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

22393

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.0

(source)

DANN

Benign

0.50

PhyloP100

0.46

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