dbSNP rs587776937: GRIA1:p.Ala636Thr (chr5-153764516-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000827.4(GRIA1):c.1906G>A(p.Ala636Thr) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

GRIA1
NM_000827.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.77

Publications

16 publications found

Variant links:

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)

GRIA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 5-153764516-G-A is Pathogenic according to our data. Variant chr5-153764516-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIA1	NM_000827.4	MANE Select	c.1906G>A	p.Ala636Thr	missense	Exon 12 of 16	NP_000818.2	P42261-1
GRIA1	NM_001258021.2		c.1936G>A	p.Ala646Thr	missense	Exon 12 of 16	NP_001244950.1	P42261-5
GRIA1	NM_001258022.2		c.1936G>A	p.Ala646Thr	missense	Exon 12 of 16	NP_001244951.1	P42261-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIA1	ENST00000285900.10	TSL:1 MANE Select	c.1906G>A	p.Ala636Thr	missense	Exon 12 of 16	ENSP00000285900.4	P42261-1
GRIA1	ENST00000340592.10	TSL:1	c.1906G>A	p.Ala636Thr	missense	Exon 12 of 16	ENSP00000339343.5	P42261-2
GRIA1	ENST00000706733.1		c.1906G>A	p.Ala636Thr	missense	Exon 12 of 17	ENSP00000516520.1	A0A9L9PYA4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual developmental disorder, autosomal dominant 67 (6)

not provided (2)

Intellectual developmental disorder, autosomal dominant 67;C5677007:Intellectual developmental disorder, autosomal recessive 76 (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.0

PhyloP100

9.8

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.87

Gain of glycosylation at A636 (P = 0.0806)

MVP

0.94

MPC

2.4

ClinPred

0.99

GERP RS

5.3

Varity_R

0.76

gMVP

0.97

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over