X-123185881-T-G

Position:

• chrX-123185881-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000828.5(GRIA3):​c.159T>G​(p.Phe53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. F53F) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GRIA3 NM_000828.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.159T>G	p.Phe53Leu	missense_variant	2/16	ENST00000622768.5
GRIA3	NM_007325.5	c.159T>G	p.Phe53Leu	missense_variant	2/16	ENST00000620443.2
GRIA3	NM_001256743.2	c.159T>G	p.Phe53Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.159T>G	p.Phe53Leu	missense_variant	2/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.159T>G	p.Phe53Leu	missense_variant	2/16	5	NM_000828.5	A1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	.;D;D;D;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.39	.;N;.;.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.8	.;.;.;.;D;.
REVEL	Uncertain	0.63
Sift	Benign	0.081	.;.;.;.;T;.
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.96, 0.95	.;D;.;.;D;P
Vest4		0.54
MutPred		0.66		Loss of methylation at R52 (P = 0.2169);Loss of methylation at R52 (P = 0.2169);Loss of methylation at R52 (P = 0.2169);Loss of methylation at R52 (P = 0.2169);Loss of methylation at R52 (P = 0.2169);Loss of methylation at R52 (P = 0.2169);
MVP		0.97
ClinPred		0.81	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.89

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: rs145583732; hg19: chrX-122319733;