chrX-123417394-T-A

Position:

chrX-123417394-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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:8

Conservation

PhyloP100: 0.804

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 4 XL gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2 linkuse as main transcript	c.1501-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_007325.5	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.1501-8T>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5	NM_000828.5	A1	P42263-1
GRIA3	ENST00000620581.4 linkuse as main transcript	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.:

Cov.:

AF XY:

0.00883

AC XY:

302

AN XY:

34184

show subpopulations

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.:

AF XY:

0.00860

AC XY:

564

AN XY:

65562

show subpopulations

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.:

Cov.:

AF XY:

0.00818

AC XY:

2869

AN XY:

350651

show subpopulations

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.:

Cov.:

AF XY:

0.00885

AC XY:

303

AN XY:

34243

show subpopulations

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.:

Bravo

AF:

0.00637

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over