X-123186065-T-C

Position:

• chrX-123186065-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.268+75T>C		intron_variant		ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.268+75T>C		intron_variant		ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2	c.268+75T>C		intron_variant			NP_001243672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.268+75T>C		intron_variant		1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.268+75T>C		intron_variant		5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 38627 AN: 110423 Hom.: 5105 Cov.: 22 AF XY: 0.342 AC XY: 11176 AN XY: 32719

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

Gnomad4 AFR exome AF: 0.274

Gnomad4 AMR exome AF: 0.413

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.696

Gnomad4 SAS exome AF: 0.485

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.397

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

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.368

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.467

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.376

Alfa AF: 0.354 Hom.: 3638

Bravo AF: 0.360

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.6
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs2269551; hg19: chrX-122319917; COSMIC: COSV52053048;