X-123184555-T-C

Variant names:

• chrX-123184555-T-C
• NM_000828.5:c.20T>C

Variant summary

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

The NM_007325.5(GRIA3):​c.20T>C​(p.Met7Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,096,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: GRIA3 NM_007325.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.70

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 rank	MANE	Protein	UniProt
GRIA3	NM_000828.5	c.20T>C	p.Met7Thr	missense_variant	Exon 1 of 16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5	c.20T>C	p.Met7Thr	missense_variant	Exon 1 of 16	ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2	c.20T>C	p.Met7Thr	missense_variant	Exon 1 of 4		NP_001243672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2	c.20T>C	p.Met7Thr	missense_variant	Exon 1 of 16	1	NM_007325.5	ENSP00000478489.1
GRIA3	ENST00000622768.5	c.20T>C	p.Met7Thr	missense_variant	Exon 1 of 16	5	NM_000828.5	ENSP00000481554.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096466 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361880

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: 0.00000476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 31, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M7T variant (also known as c.20T>C), located in coding exon 1 of the GRIA3 gene, results from a T to C substitution at nucleotide position 20. The methionine at codon 7 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	.;T;T;T;.;T
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;.;.;L;L
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.72, 0.81	.;P;.;.;P;P
Vest4		0.86
MutPred		0.46		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP		1.0
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-122318407;