NM_000828.5:c.268+16606T>A

Variant names:

• chrX-123202596-T-A
• rs2285127
• NM_000828.5:c.268+16606T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000828.5(GRIA3):​c.268+16606T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,152,103 control chromosomes in the GnomAD database, including 3 homozygotes. There are 465 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 0.00059 (0 hom., 18 hem., cov: 23)
  • Exomes 𝑓: 0.00091 (3 hom. 447 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS2: High Hemizygotes in GnomAd4 at 18 XL gene

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>A		intron	N/A	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.268+16606T>A		intron	N/A	NP_015564.5
	GRIA3	NM_001256743.2		c.269-40T>A		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>A		intron	N/A	ENSP00000478489.1
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.268+16606T>A		intron	N/A	ENSP00000481554.1
	GRIA3	ENST00000611689.4	TSL:1	c.269-40T>A		intron	N/A	ENSP00000478758.1

Frequencies

GnomAD3 genomes AF: 0.000577 AC: 64 AN: 110968 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.000379

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00713

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.000680

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.00166 AC: 169 AN: 101601 AF XY: 0.00234

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.000363

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000909 AC: 946 AN: 1041084 Hom.: 3 Cov.: 25 AF XY: 0.00134 AC XY: 447 AN XY: 334128

African (AFR) AF: 0.0000405 AC: 1 AN: 24675

American (AMR) AF: 0.000362 AC: 10 AN: 27605

Ashkenazi Jewish (ASJ) AF: 0.000491 AC: 9 AN: 18319

East Asian (EAS) AF: 0.000296 AC: 8 AN: 27021

South Asian (SAS) AF: 0.0108 AC: 525 AN: 48675

European-Finnish (FIN) AF: 0.0000273 AC: 1 AN: 36674

Middle Eastern (MID) AF: 0.00791 AC: 26 AN: 3287

European-Non Finnish (NFE) AF: 0.000381 AC: 309 AN: 811009

Other (OTH) AF: 0.00130 AC: 57 AN: 43819

GnomAD4 genome AF: 0.000585 AC: 65 AN: 111019 Hom.: 0 Cov.: 23 AF XY: 0.000541 AC XY: 18 AN XY: 33251

African (AFR) AF: 0.0000657 AC: 2 AN: 30441

American (AMR) AF: 0.0000951 AC: 1 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.000379 AC: 1 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3454

South Asian (SAS) AF: 0.00752 AC: 20 AN: 2658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5989

Middle Eastern (MID) AF: 0.0142 AC: 3 AN: 211

European-Non Finnish (NFE) AF: 0.000680 AC: 36 AN: 52924

Other (OTH) AF: 0.00132 AC: 2 AN: 1515

Alfa AF: 0.000490 Hom.: 3944

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.21
DANN	Benign	0.83
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;