rs139058646

chrX-123417394-T-AchrX-123417394-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000828.5(GRIA3):c.1501-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,195,768 control chromosomes in the GnomAD database, including 38 homozygotes. There are 3,172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (4 hom., 303 hem., cov: 23)
  • Exomes 𝑓: 0.0084 (34 hom. 2869 hem.)
• Consequence: GRIA3 NM_000828.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002496
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.804

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-123417394-T-A is Benign according to our data. Variant chrX-123417394-T-A is described in ClinVar as [Benign]. Clinvar id is 129168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-123417394-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00784 (879/112073) while in subpopulation AMR AF= 0.0115 (121/10561). AF 95% confidence interval is 0.0098. There are 4 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.1501-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000622768.5
GRIA3	NM_007325.5	c.1501-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.1501-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.1501-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.1501-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 880 AN: 112024 Hom.: 3 Cov.: 23 AF XY: 0.00883 AC XY: 302 AN XY: 34184

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.0112

GnomAD3 exomes AF: 0.00832 AC: 1498 AN: 180082 Hom.: 7 AF XY: 0.00860 AC XY: 564 AN XY: 65562

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00650

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.00884

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00838 AC: 9080 AN: 1083695 Hom.: 34 Cov.: 27 AF XY: 0.00818 AC XY: 2869 AN XY: 350651

Gnomad4 AFR exome AF: 0.00142

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.00151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00746

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.00838

Gnomad4 OTH exome AF: 0.00723

GnomAD4 genome AF: 0.00784 AC: 879 AN: 112073 Hom.: 4 Cov.: 23 AF XY: 0.00885 AC XY: 303 AN XY: 34243

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.0315

Gnomad4 NFE AF: 0.00914

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00369 Hom.: 27

Bravo AF: 0.00637

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	7.3
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.014
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: rs139058646; hg19: chrX-122551245; COSMIC: COSV105859121;