X-123481804-T-C

Variant names:

• chrX-123481804-T-C
• rs5910006
• NM_000828.5:c.2440-995T>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.2440-995T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 111,107 control chromosomes in the GnomAD database, including 5,570 homozygotes. There are 12,092 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 0.36 (5570 hom., 12092 hem., cov: 23)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 6 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=-0.51).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000828.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.2440-995T>C		intron	N/A	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.2440-995T>C		intron	N/A	NP_015564.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.2440-995T>C		intron	N/A	ENSP00000478489.1
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.2440-995T>C		intron	N/A	ENSP00000481554.1
	GRIA3	ENST00000620581.4	TSL:1	n.*80-995T>C		intron	N/A	ENSP00000481875.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 40041 AN: 111056 Hom.: 5577 Cov.: 23

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.527

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.362

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

GnomAD4 genome AF: 0.360 AC: 40025 AN: 111107 Hom.: 5570 Cov.: 23 AF XY: 0.363 AC XY: 12092 AN XY: 33313

African (AFR) AF: 0.183 AC: 5599 AN: 30670

American (AMR) AF: 0.402 AC: 4223 AN: 10501

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1135 AN: 2635

East Asian (EAS) AF: 0.313 AC: 1096 AN: 3497

South Asian (SAS) AF: 0.527 AC: 1376 AN: 2612

European-Finnish (FIN) AF: 0.442 AC: 2601 AN: 5890

Middle Eastern (MID) AF: 0.403 AC: 87 AN: 216

European-Non Finnish (NFE) AF: 0.438 AC: 23192 AN: 52895

Other (OTH) AF: 0.358 AC: 541 AN: 1510

Alfa AF: 0.414 Hom.: 47963

Bravo AF: 0.350

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.1
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: rs5910006; hg19: chrX-122615655;