11-105612350-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000829.4(GRIA4):c.163C>T(p.Pro55Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

GRIA4 (HGNC:4574): (glutamate ionotropic receptor AMPA type subunit 4) 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 of this gene results in transcript variants encoding different isoforms, which may vary in their signal transduction properties. Some haplotypes of this gene show a positive association with schizophrenia. [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
• PP2: Missense variant where missense usually causes diseases, GRIA4
• BP4: Computational evidence support a benign effect (MetaRNN=0.38955808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA4	NM_000829.4	c.163C>T	p.Pro55Ser	missense_variant	3/17	ENST00000282499.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA4	ENST00000282499.10	c.163C>T	p.Pro55Ser	missense_variant	3/17	5	NM_000829.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 03, 2024

The c.163C>T (p.P55S) alteration is located in exon 3 (coding exon 2) of the GRIA4 gene. This alteration results from a C to T substitution at nucleotide position 163, causing the proline (P) at amino acid position 55 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.020	N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D;T;D;T;T;D;D;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.027, 0.92	.;.;.;B;P;.;.;.;.;P;B
Vest4		0.64, 0.66, 0.69, 0.68, 0.64, 0.66
MutPred		0.47		Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);Gain of catalytic residue at P55 (P = 0.0633);
MVP		0.45
MPC		0.31
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.081
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-105483077;