rs1555050158

Variant names:

• chr11-105926808-A-T
• rs1555050158
• NM_000829.4:c.1915A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000829.4(GRIA4):​c.1915A>T​(p.Thr639Ser) 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 Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA4 NM_000829.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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]

GRIA4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with or without seizures and gait abnormalities

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000829.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 11-105926808-A-T is Pathogenic according to our data. Variant chr11-105926808-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 446206.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000829.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA4	NM_000829.4	MANE Select	c.1915A>T	p.Thr639Ser	missense	Exon 13 of 17	NP_000820.4
	GRIA4	NM_001440382.1		c.1915A>T	p.Thr639Ser	missense	Exon 13 of 17	NP_001427311.1
	GRIA4	NM_001440383.1		c.1915A>T	p.Thr639Ser	missense	Exon 13 of 17	NP_001427312.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA4	ENST00000282499.10	TSL:5 MANE Select	c.1915A>T	p.Thr639Ser	missense	Exon 13 of 17	ENSP00000282499.5
	GRIA4	ENST00000530497.1	TSL:1	c.1915A>T	p.Thr639Ser	missense	Exon 12 of 16	ENSP00000435775.1
	GRIA4	ENST00000525187.6	TSL:1	c.1915A>T	p.Thr639Ser	missense	Exon 13 of 17	ENSP00000432180.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neurodevelopmental disorder with or without seizures and gait abnormalities Pathogenic:1

Feb 07, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Intellectual disability Pathogenic:1

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.87		Loss of helix (P = 0.1299)
MVP		0.87
MPC		2.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.91
gMVP		0.90
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555050158; hg19: chr11-105797534;