5-153494002-C-T

Variant names:

• chr5-153494002-C-T
• NM_000827.4:c.157C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000827.4(GRIA1):​c.157C>T​(p.Pro53Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P53L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRIA1 NM_000827.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37
• Publications: 0 publications found

Genes affected

GRIA1 (HGNC:4571): (glutamate ionotropic receptor AMPA type subunit 1) 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 with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. This gene belongs to a family of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GRIA1 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, autosomal dominant 67

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: ClinGen
• intellectual developmental disorder, autosomal recessive 76

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000827.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA1	NM_000827.4	MANE Select	c.157C>T	p.Pro53Ser	missense	Exon 2 of 16	NP_000818.2	P42261-1
	GRIA1	NM_001258021.2		c.187C>T	p.Pro63Ser	missense	Exon 2 of 16	NP_001244950.1	P42261-5
	GRIA1	NM_001258022.2		c.187C>T	p.Pro63Ser	missense	Exon 2 of 16	NP_001244951.1	P42261-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA1	ENST00000285900.10	TSL:1 MANE Select	c.157C>T	p.Pro53Ser	missense	Exon 2 of 16	ENSP00000285900.4	P42261-1
	GRIA1	ENST00000340592.10	TSL:1	c.157C>T	p.Pro53Ser	missense	Exon 2 of 16	ENSP00000339343.5	P42261-2
	GRIA1	ENST00000481559.6	TSL:1	n.298C>T		non_coding_transcript_exon	Exon 2 of 11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual developmental disorder, autosomal dominant 67 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.17
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.62	P
Vest4		0.65
MutPred		0.35		Loss of catalytic residue at P52 (P = 0.0101)
MVP		0.46
MPC		0.82
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.72
Mutation Taster		=47/53	disease causing

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

Other links and lift over

hg19: chr5-152873562;