NM_000828.5:c.1964T>C

Variant names:

• chrX-123428027-T-C
• rs1135401788
• NM_000828.5:c.1964T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000828.5(GRIA3):​c.1964T>C​(p.Phe655Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F655F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability 94

  Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked intellectual disability due to GRIA3 anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307341 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000828.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked complex neurodevelopmental disorder, syndromic X-linked intellectual disability 94, X-linked intellectual disability due to GRIA3 anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-123428027-T-C is Pathogenic according to our data. Variant chrX-123428027-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 431114.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.1964T>C	p.Phe655Ser	missense_variant	Exon 12 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.1964T>C	p.Phe655Ser	missense_variant	Exon 12 of 16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.1964T>C	p.Phe655Ser	missense_variant	Exon 12 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.1964T>C	p.Phe655Ser	missense_variant	Exon 12 of 16	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability 94 Pathogenic:1

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, severe; hypotonia -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;T;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.050	D
MutationAssessor	Pathogenic	3.1	M;.;M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;.;D;D
Vest4		0.98
MutPred		0.89		Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);Loss of stability (P = 0.0035);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.99
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1135401788; hg19: chrX-122561878;