rs10521721

Variant names:

• chrX-123444322-T-C
• rs10521721
• NM_000828.5:c.2076+16183T>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.2076+16183T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 110,788 control chromosomes in the GnomAD database, including 726 homozygotes. There are 3,809 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 0.12 (726 hom., 3809 hem., cov: 22)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.2076+16183T>C		intron_variant	Intron 12 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.2076+16183T>C		intron_variant	Intron 12 of 15	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.2076+16183T>C		intron_variant	Intron 12 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.2076+16183T>C		intron_variant	Intron 12 of 15	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 13780 AN: 110734 Hom.: 730 Cov.: 22

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.105

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.124 AC: 13769 AN: 110788 Hom.: 726 Cov.: 22 AF XY: 0.115 AC XY: 3809 AN XY: 33040

African (AFR) AF: 0.0627 AC: 1918 AN: 30588

American (AMR) AF: 0.204 AC: 2125 AN: 10404

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 290 AN: 2637

East Asian (EAS) AF: 0.0461 AC: 162 AN: 3514

South Asian (SAS) AF: 0.112 AC: 289 AN: 2569

European-Finnish (FIN) AF: 0.113 AC: 666 AN: 5882

Middle Eastern (MID) AF: 0.110 AC: 24 AN: 218

European-Non Finnish (NFE) AF: 0.152 AC: 7998 AN: 52791

Other (OTH) AF: 0.130 AC: 195 AN: 1504

Alfa AF: 0.146 Hom.: 10705

Bravo AF: 0.129

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.85
PhyloP100		-1.3
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: rs10521721; hg19: chrX-122578173;