X-123273171-T-C

Variant names:

• chrX-123273171-T-C
• rs5909981
• NM_000828.5:c.508+19629T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000828.5(GRIA3):​c.508+19629T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 110,430 control chromosomes in the GnomAD database, including 7,721 homozygotes. There are 12,165 hemizygotes 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 0.39 (7721 hom., 12165 hem., cov: 22)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.610
• Publications: 0 publications found

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

ENSG00000307341 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.508+19629T>C		intron_variant	Intron 3 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.508+19629T>C		intron_variant	Intron 3 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.508+19629T>C		intron_variant	Intron 3 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.508+19629T>C		intron_variant	Intron 3 of 15	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.508+19629T>C		intron_variant	Intron 3 of 16	1		ENSP00000481875.1
ENSG00000307341	ENST00000825206.1	n.667+40674A>G		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes AF: 0.390 AC: 43007 AN: 110376 Hom.: 7713 Cov.: 22

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.390 AC: 43080 AN: 110430 Hom.: 7721 Cov.: 22 AF XY: 0.372 AC XY: 12165 AN XY: 32720

African (AFR) AF: 0.700 AC: 21100 AN: 30152

American (AMR) AF: 0.319 AC: 3325 AN: 10430

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 652 AN: 2640

East Asian (EAS) AF: 0.397 AC: 1371 AN: 3455

South Asian (SAS) AF: 0.249 AC: 645 AN: 2589

European-Finnish (FIN) AF: 0.292 AC: 1723 AN: 5902

Middle Eastern (MID) AF: 0.226 AC: 49 AN: 217

European-Non Finnish (NFE) AF: 0.256 AC: 13527 AN: 52860

Other (OTH) AF: 0.377 AC: 566 AN: 1503

Alfa AF: 0.311 Hom.: 36792

Bravo AF: 0.410

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.76
DANN	Benign	0.42
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5909981; hg19: chrX-122407022;