5-153764516-G-A

Position:

• chr5-153764516-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000827.4(GRIA1):​c.1906G>A​(p.Ala636Thr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA1 NM_000827.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.77

Genes affected

GRIA1 (HGNC:4571): (glutamate ionotropic receptor AMPA type subunit 1) 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 with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GRIA1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRIA1. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 4.3518 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder, autosomal dominant 67, intellectual developmental disorder, autosomal recessive 76.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 5-153764516-G-A is Pathogenic according to our data. Variant chr5-153764516-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-153764516-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA1	NM_000827.4	c.1906G>A	p.Ala636Thr	missense_variant	12/16	ENST00000285900.10	NP_000818.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA1	ENST00000285900.10	c.1906G>A	p.Ala636Thr	missense_variant	12/16	1	NM_000827.4	ENSP00000285900.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder, autosomal dominant 67 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	Sep 29, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 15, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	May 11, 2023	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jun 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2022	Published functional studies demonstrate a damaging effect on channel desensitization (Taverna et al., 2000; Islail et al. 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23033978, 28628100, 28191890, 31587869, 29220673, 31300657, 31785789, 20089915, 35887114, 35409220, Murtaza2022[functionalstudy], 35675825, 20048760, 10722683, 28714951) -

Intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand

May 17, 2021

PS2 + PS3 + PM2 + PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.5	D;D;D;.;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.
Vest4		0.97
MutPred		0.87		Gain of glycosylation at A636 (P = 0.0806);.;Gain of glycosylation at A636 (P = 0.0806);.;.;.;
MVP		0.94
MPC		2.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.76
gMVP		0.97

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: rs587776937; hg19: chr5-153144076; COSMIC: COSV53598273;