NM_000828.5:c.397G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_000828.5(GRIA3):c.397G>A(p.Ala133Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,209,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 82 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., 30 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 52 hem. )

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.88

Publications

1 publications found

Variant links:

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]

GRIA3 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 94
Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability due to GRIA3 anomalies
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GRIA3 links:

ENSG00000307341 (HGNC:):

ENSG00000307341 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked complex neurodevelopmental disorder, syndromic X-linked intellectual disability 94, X-linked intellectual disability due to GRIA3 anomalies.

BP4

Computational evidence support a benign effect (MetaRNN=0.008761585).

BP6

Variant X-123253431-G-A is Benign according to our data. Variant chrX-123253431-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 281521.

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000828.5. 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
	GRIA3	NM_000828.5	MANE Plus Clinical	c.397G>A	p.Ala133Thr	missense	Exon 3 of 16	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.397G>A	p.Ala133Thr	missense	Exon 3 of 16	NP_015564.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.397G>A	p.Ala133Thr	missense	Exon 3 of 16	ENSP00000478489.1	P42263-2
GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.397G>A	p.Ala133Thr	missense	Exon 3 of 16	ENSP00000481554.1	P42263-1
GRIA3	ENST00000620581.4	TSL:1	n.397G>A		non_coding_transcript_exon	Exon 3 of 17	ENSP00000481875.1	A0A087WYJ6

Frequencies

GnomAD3 genomes

AF:

0.000787

AC:

AN:

111762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000377

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.00134

GnomAD2 exomes

AF:

0.000349

AC:

AN:

183345

AF XY:

0.000295

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000155

AC:

170

AN:

1097577

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

362943

show subpopulations

African (AFR)

AF:

0.00201

AC:

AN:

26388

American (AMR)

AF:

0.000142

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30203

South Asian (SAS)

AF:

0.000997

AC:

AN:

54136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40499

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000499

AC:

AN:

841560

Other (OTH)

AF:

0.000304

AC:

AN:

46077

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000787

AC:

AN:

111817

Hom.:

Cov.:

AF XY:

0.000882

AC XY:

AN XY:

33999

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

30789

American (AMR)

AF:

0.00

AC:

AN:

10570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3518

South Asian (SAS)

AF:

0.000378

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53157

Other (OTH)

AF:

0.00132

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.000827

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

History of neurodevelopmental disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.017

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-1.0

PhyloP100

2.9

PrimateAI

Uncertain

0.79

REVEL

Benign

0.29

Sift4G

Benign

0.93

Polyphen

0.0020

Vest4

0.067

MVP

0.70

ClinPred

0.012

GERP RS

5.5

Varity_R

0.20

gMVP

0.36

Mutation Taster

=95/5

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over