rs502434

chrX-123403426-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000828.5(GRIA3):c.1200T>C(p.Asn400=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (12338 hom., 18554 hem., cov: 23)
  • Exomes 𝑓: 0.59 (130711 hom. 197798 hem.)
  • Failed GnomAD Quality Control
• Consequence: GRIA3 NM_000828.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.14

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-123403426-T-C is Benign according to our data. Variant chrX-123403426-T-C is described in ClinVar as [Benign]. Clinvar id is 129167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-123403426-T-C is described in Lovd as [Benign]. Variant chrX-123403426-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 12341 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.1200T>C	p.Asn400=	synonymous_variant	9/16	ENST00000622768.5
GRIA3	NM_007325.5	c.1200T>C	p.Asn400=	synonymous_variant	9/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.1200T>C	p.Asn400=	synonymous_variant	9/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.1200T>C	p.Asn400=	synonymous_variant	9/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.1200T>C	p.Asn400=	synonymous_variant, NMD_transcript_variant	9/17	1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 61905 AN: 110644 Hom.: 12341 Cov.: 23 AF XY: 0.563 AC XY: 18520 AN XY: 32906

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.548

GnomAD3 exomes AF: 0.587 AC: 107501 AN: 183055 Hom.: 20189 AF XY: 0.587 AC XY: 39666 AN XY: 67617

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.638

Gnomad EAS exome AF: 0.611

Gnomad SAS exome AF: 0.459

Gnomad FIN exome AF: 0.737

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.602

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.594 AC: 630466 AN: 1061632 Hom.: 130711 Cov.: 27 AF XY: 0.585 AC XY: 197798 AN XY: 338076

Gnomad4 AFR exome AF: 0.439

Gnomad4 AMR exome AF: 0.559

Gnomad4 ASJ exome AF: 0.640

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.461

Gnomad4 FIN exome AF: 0.726

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.581

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.559 AC: 61934 AN: 110702 Hom.: 12338 Cov.: 23 AF XY: 0.563 AC XY: 18554 AN XY: 32974

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.572

Gnomad4 ASJ AF: 0.644

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.730

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.554

Alfa AF: 0.597 Hom.: 29059

Bravo AF: 0.551

EpiCase AF: 0.608

EpiControl AF: 0.614

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Syndromic X-linked intellectual disability 94 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.3
Dann	Benign	0.72

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: rs502434; hg19: chrX-122537277; COSMIC: COSV52076814;