rs2269551

Variant names:

• chrX-123186065-T-C
• rs2269551
• NM_000828.5:c.268+75T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-123186065-T-C
• chrX-123186065-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007325.5(GRIA3):​c.268+75T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 844,117 control chromosomes in the GnomAD database, including 45,981 homozygotes. There are 99,862 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (5101 hom., 11181 hem., cov: 22)
  • Exomes 𝑓: 0.40 (40880 hom. 88681 hem.)
• Consequence: GRIA3 NM_007325.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.119
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-123186065-T-C is Benign according to our data. Variant chrX-123186065-T-C is described in ClinVar as Benign. ClinVar VariationId is 1259476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007325.5. 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+75T>C		intron	N/A	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.268+75T>C		intron	N/A	NP_015564.5
	GRIA3	NM_001256743.2		c.268+75T>C		intron	N/A	NP_001243672.1	Q5XKG2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.268+75T>C		intron	N/A	ENSP00000478489.1	P42263-2
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.268+75T>C		intron	N/A	ENSP00000481554.1	P42263-1
	GRIA3	ENST00000611689.4	TSL:1	c.268+75T>C		intron	N/A	ENSP00000478758.1	Q5XKG2

Frequencies

GnomAD3 genomes AF: 0.350 AC: 38627 AN: 110423 Hom.: 5105 Cov.: 22

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.504

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.399 AC: 292811 AN: 733637 Hom.: 40880 AF XY: 0.433 AC XY: 88681 AN XY: 204883

African (AFR) AF: 0.274 AC: 5260 AN: 19221

American (AMR) AF: 0.413 AC: 14141 AN: 34256

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 6698 AN: 17059

East Asian (EAS) AF: 0.696 AC: 19808 AN: 28467

South Asian (SAS) AF: 0.485 AC: 22572 AN: 46513

European-Finnish (FIN) AF: 0.300 AC: 11769 AN: 39234

Middle Eastern (MID) AF: 0.401 AC: 1383 AN: 3448

European-Non Finnish (NFE) AF: 0.386 AC: 197633 AN: 511357

Other (OTH) AF: 0.397 AC: 13547 AN: 34082

GnomAD4 genome AF: 0.350 AC: 38617 AN: 110480 Hom.: 5101 Cov.: 22 AF XY: 0.341 AC XY: 11181 AN XY: 32786

African (AFR) AF: 0.265 AC: 8034 AN: 30324

American (AMR) AF: 0.368 AC: 3844 AN: 10450

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1022 AN: 2616

East Asian (EAS) AF: 0.653 AC: 2269 AN: 3473

South Asian (SAS) AF: 0.467 AC: 1167 AN: 2501

European-Finnish (FIN) AF: 0.282 AC: 1677 AN: 5939

Middle Eastern (MID) AF: 0.500 AC: 108 AN: 216

European-Non Finnish (NFE) AF: 0.371 AC: 19572 AN: 52789

Other (OTH) AF: 0.376 AC: 565 AN: 1502

Alfa AF: 0.330 Hom.: 4821

Bravo AF: 0.360

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.61
PhyloP100		0.12
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: rs2269551; hg19: chrX-122319917; COSMIC: COSV52053048;