X-123202596-T-C

Variant names:

• chrX-123202596-T-C
• rs2285127
• NM_000828.5:c.268+16606T>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.268+16606T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 1,151,262 control chromosomes in the GnomAD database, including 54,013 homozygotes. There are 134,888 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 0.38 (5848 hom., 12330 hem., cov: 23)
  • Exomes 𝑓: 0.37 (48165 hom. 122558 hem.)
• Consequence: GRIA3 NM_000828.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 7 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.458 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.268+16606T>C		intron	N/A	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.268+16606T>C		intron	N/A	NP_015564.5
	GRIA3	NM_001256743.2		c.269-40T>C		intron	N/A	NP_001243672.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.268+16606T>C		intron	N/A	ENSP00000478489.1
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.268+16606T>C		intron	N/A	ENSP00000481554.1
	GRIA3	ENST00000611689.4	TSL:1	c.269-40T>C		intron	N/A	ENSP00000478758.1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 42346 AN: 110911 Hom.: 5848 Cov.: 23

Gnomad AFR AF: 0.406

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.391

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.466

Gnomad NFE AF: 0.356

Gnomad OTH AF: 0.388

GnomAD2 exomes AF: 0.405 AC: 41117 AN: 101601 AF XY: 0.394

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.535

Gnomad ASJ exome AF: 0.401

Gnomad EAS exome AF: 0.486

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.366 AC: 381207 AN: 1040301 Hom.: 48165 Cov.: 25 AF XY: 0.367 AC XY: 122558 AN XY: 334079

African (AFR) AF: 0.410 AC: 10123 AN: 24665

American (AMR) AF: 0.523 AC: 14425 AN: 27594

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 7492 AN: 18303

East Asian (EAS) AF: 0.485 AC: 13110 AN: 27011

South Asian (SAS) AF: 0.405 AC: 19722 AN: 48649

European-Finnish (FIN) AF: 0.292 AC: 10703 AN: 36671

Middle Eastern (MID) AF: 0.382 AC: 1254 AN: 3286

European-Non Finnish (NFE) AF: 0.355 AC: 287823 AN: 810331

Other (OTH) AF: 0.378 AC: 16555 AN: 43791

GnomAD4 genome AF: 0.382 AC: 42366 AN: 110961 Hom.: 5848 Cov.: 23 AF XY: 0.371 AC XY: 12330 AN XY: 33223

African (AFR) AF: 0.406 AC: 12359 AN: 30416

American (AMR) AF: 0.452 AC: 4748 AN: 10509

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1084 AN: 2636

East Asian (EAS) AF: 0.477 AC: 1646 AN: 3453

South Asian (SAS) AF: 0.388 AC: 1030 AN: 2656

European-Finnish (FIN) AF: 0.272 AC: 1628 AN: 5985

Middle Eastern (MID) AF: 0.455 AC: 96 AN: 211

European-Non Finnish (NFE) AF: 0.356 AC: 18813 AN: 52906

Other (OTH) AF: 0.392 AC: 594 AN: 1515

Alfa AF: 0.309 Hom.: 3944

Bravo AF: 0.404

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.27
DANN	Benign	0.79
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: rs2285127; hg19: chrX-122336448; COSMIC: COSV52085355;