rs138817389

Positions:

• chrX-123403094-G-A
• chrX-123403094-G-T

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.1181G>A​(p.Arg394Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,036,915 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 369 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.0010 (0 hom. 343 hem.)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.60

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 (MetaRNN=0.0107678175).
• BP6: Variant X-123403094-G-A is Benign according to our data. Variant chrX-123403094-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-123403094-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0009 (101/112168) while in subpopulation SAS AF= 0.00259 (7/2700). AF 95% confidence interval is 0.00122. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.1181G>A	p.Arg394Gln	missense_variant	8/16	ENST00000622768.5
GRIA3	NM_007325.5	c.1181G>A	p.Arg394Gln	missense_variant	8/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.1181G>A	p.Arg394Gln	missense_variant	8/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.1181G>A	p.Arg394Gln	missense_variant	8/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.1181G>A	p.Arg394Gln	missense_variant, NMD_transcript_variant	8/17	1

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 101 AN: 112111 Hom.: 0 Cov.: 22 AF XY: 0.000757 AC XY: 26 AN XY: 34343

Gnomad AFR AF: 0.0000973

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000567

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00259

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00268

GnomAD3 exomes AF: 0.00148 AC: 271 AN: 183088 Hom.: 1 AF XY: 0.00170 AC XY: 115 AN XY: 67650

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000804

Gnomad ASJ exome AF: 0.00749

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00289

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00104 AC: 959 AN: 924747 Hom.: 0 Cov.: 17 AF XY: 0.00137 AC XY: 343 AN XY: 251247

Gnomad4 AFR exome AF: 0.000129

Gnomad4 AMR exome AF: 0.000803

Gnomad4 ASJ exome AF: 0.00749

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.0000249

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000900 AC: 101 AN: 112168 Hom.: 0 Cov.: 22 AF XY: 0.000756 AC XY: 26 AN XY: 34410

Gnomad4 AFR AF: 0.0000971

Gnomad4 AMR AF: 0.000567

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00259

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00145 Hom.: 63

Bravo AF: 0.000929

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00193 AC: 13

ExAC AF: 0.00161 AC: 195

EpiCase AF: 0.00164

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jun 11, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Syndromic X-linked intellectual disability 94 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

GRIA3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.38
MVP		1.0
ClinPred		0.037	T
GERP RS		5.7
Varity_R		0.46
gMVP		0.68

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: rs138817389; hg19: chrX-122536945; COSMIC: COSV52051792;