rs146022384

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.1166A>C(p.Lys389Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00057 in 1,122,978 control chromosomes in the GnomAD database, including 2 homozygotes. There are 199 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., 35 hem., cov: 23)

Exomes 𝑓: 0.00054 ( 2 hom. 164 hem. )

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.86

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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=0.011986196).

BP6

Variant X-123403079-A-C is Benign according to our data. Variant chrX-123403079-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 493545.

BS2

High Hemizygotes in GnomAd4 at 35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.1166A>C	p.Lys389Thr	missense	Exon 8 of 16	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.1166A>C	p.Lys389Thr	missense	Exon 8 of 16	NP_015564.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.1166A>C	p.Lys389Thr	missense	Exon 8 of 16	ENSP00000478489.1
GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.1166A>C	p.Lys389Thr	missense	Exon 8 of 16	ENSP00000481554.1
GRIA3	ENST00000620581.4	TSL:1	n.1166A>C		non_coding_transcript_exon	Exon 8 of 17	ENSP00000481875.1

Frequencies

GnomAD3 genomes

AF:

0.000871

AC:

AN:

112496

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000943

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00387

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00133

Gnomad OTH

AF:

0.000662

GnomAD2 exomes

AF:

0.000791

AC:

145

AN:

183214

AF XY:

0.000768

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.000770

Gnomad OTH exome

AF:

0.000443

GnomAD4 exome

AF:

0.000536

AC:

542

AN:

1010427

Hom.:

Cov.:

AF XY:

0.000555

AC XY:

164

AN XY:

295625

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24761

American (AMR)

AF:

0.000228

AC:

AN:

35019

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18721

East Asian (EAS)

AF:

0.00

AC:

AN:

29701

South Asian (SAS)

AF:

0.00

AC:

AN:

52144

European-Finnish (FIN)

AF:

0.00394

AC:

159

AN:

40313

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3921

European-Non Finnish (NFE)

AF:

0.000465

AC:

355

AN:

762741

Other (OTH)

AF:

0.000464

AC:

AN:

43106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

101

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:

0.000871

AC:

AN:

112551

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

34725

show subpopulations

African (AFR)

AF:

0.0000322

AC:

AN:

31030

American (AMR)

AF:

0.0000942

AC:

AN:

10621

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3612

South Asian (SAS)

AF:

0.00

AC:

AN:

2720

European-Finnish (FIN)

AF:

0.00387

AC:

AN:

6203

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00133

AC:

AN:

53276

Other (OTH)

AF:

0.000654

AC:

AN:

1529

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:

0.000933

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 02, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Oct 12, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.037

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

4.9

PrimateAI

Pathogenic

0.80

REVEL

Benign

0.13

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.56

MVP

0.94

ClinPred

0.020

GERP RS

5.7

Varity_R

0.31

gMVP

0.79

Mutation Taster

=90/10

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over