X-123341975-T-G

Variant names:

• chrX-123341975-T-G
• rs5909995
• NM_000828.5:c.697-12935T>G

Variant summary

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

The NM_000828.5(GRIA3):​c.697-12935T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 103,123 control chromosomes in the GnomAD database, including 6,826 homozygotes. There are 12,712 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 0.44 (6826 hom., 12712 hem., cov: 21)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135
• Publications: 1 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.697-12935T>G		intron_variant	Intron 4 of 15	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.697-12935T>G		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.697-12935T>G		intron_variant	Intron 4 of 15	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.697-12935T>G		intron_variant	Intron 4 of 15	5	NM_000828.5	ENSP00000481554.1
GRIA3	ENST00000620581.4	n.697-12935T>G		intron_variant	Intron 4 of 16	1		ENSP00000481875.1
ENSG00000307341	ENST00000825206.1	n.561+14257A>C		intron_variant	Intron 5 of 6

Frequencies

GnomAD3 genomes AF: 0.435 AC: 44874 AN: 103092 Hom.: 6831 Cov.: 21

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.440

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.346

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.434

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

GnomAD4 genome AF: 0.435 AC: 44882 AN: 103123 Hom.: 6826 Cov.: 21 AF XY: 0.433 AC XY: 12712 AN XY: 29387

African (AFR) AF: 0.403 AC: 10464 AN: 25995

American (AMR) AF: 0.421 AC: 4202 AN: 9980

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1080 AN: 2586

East Asian (EAS) AF: 0.236 AC: 801 AN: 3387

South Asian (SAS) AF: 0.427 AC: 1044 AN: 2446

European-Finnish (FIN) AF: 0.435 AC: 2227 AN: 5125

Middle Eastern (MID) AF: 0.364 AC: 76 AN: 209

European-Non Finnish (NFE) AF: 0.469 AC: 24093 AN: 51320

Other (OTH) AF: 0.427 AC: 603 AN: 1411

Alfa AF: 0.445 Hom.: 10103

Bravo AF: 0.405

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.25
PhyloP100		0.14
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: rs5909995; hg19: chrX-122475826;