rs1556334045

chrX-123465109-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000828.5(GRIA3):c.2321T>C(p.Leu774Ser) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.01

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a topological_domain Extracellular (size 174) in uniprot entity GRIA3_HUMAN there are 16 pathogenic changes around while only 0 benign (100%) in NM_000828.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant X-123465109-T-C is Pathogenic according to our data. Variant chrX-123465109-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521132.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.2321T>C	p.Leu774Ser	missense_variant	13/16	ENST00000622768.5
GRIA3	NM_007325.5	c.2321T>C	p.Leu774Ser	missense_variant	13/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.2321T>C	p.Leu774Ser	missense_variant	13/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.2321T>C	p.Leu774Ser	missense_variant	13/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.2321T>C	p.Leu774Ser	missense_variant, NMD_transcript_variant	13/17	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1093081 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 358843

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Pathogenic	3.8	H;.;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.91
MutPred		0.82		Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);Gain of disorder (P = 0.0047);
MVP		1.0
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.96
gMVP		1.0

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: rs1556334045; hg19: chrX-122598960;