rs10521718

Variant names:

• chrX-123332687-G-A
• rs10521718
• NM_000828.5:c.696+6474G>A

Variant summary

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

The NM_000828.5(GRIA3):​c.696+6474G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 110,137 control chromosomes in the GnomAD database, including 1,180 homozygotes. There are 4,505 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 0.15 (1180 hom., 4505 hem., cov: 22)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.297
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.696+6474G>A		intron_variant	Intron 4 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.696+6474G>A		intron_variant	Intron 4 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.696+6474G>A		intron_variant	Intron 4 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.696+6474G>A		intron_variant	Intron 4 of 15	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.696+6474G>A		intron_variant	Intron 4 of 16	1		ENSP00000481875.1
ENSG00000307341	ENST00000825206.1	n.562-18737C>T		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.149 AC: 16358 AN: 110085 Hom.: 1181 Cov.: 22

Gnomad AFR AF: 0.0500

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.107

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.136

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

GnomAD4 genome AF: 0.148 AC: 16355 AN: 110137 Hom.: 1180 Cov.: 22 AF XY: 0.138 AC XY: 4505 AN XY: 32541

African (AFR) AF: 0.0499 AC: 1517 AN: 30410

American (AMR) AF: 0.103 AC: 1056 AN: 10300

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 445 AN: 2635

East Asian (EAS) AF: 0.0117 AC: 41 AN: 3511

South Asian (SAS) AF: 0.105 AC: 272 AN: 2584

European-Finnish (FIN) AF: 0.201 AC: 1158 AN: 5773

Middle Eastern (MID) AF: 0.108 AC: 23 AN: 212

European-Non Finnish (NFE) AF: 0.219 AC: 11525 AN: 52535

Other (OTH) AF: 0.134 AC: 202 AN: 1505

Alfa AF: 0.194 Hom.: 4336

Bravo AF: 0.136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.18
DANN	Benign	0.57
PhyloP100		-0.30
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: rs10521718; hg19: chrX-122466538;