rs752728469

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The NM_000828.5(GRIA3):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,090,266 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.000015 ( 0 hom. 6 hem. )

Consequence

GRIA3
NM_000828.5 start_lost

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.295

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 7 codons. Genomic position: 123184554. Lost 0.007 part of the original CDS.

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16	ENST00000622768.5	NP_000819.4	P42263-1Q17R51
GRIA3	NM_007325.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16	ENST00000620443.2	NP_015564.5	P42263-2Q17R51
GRIA3	NM_001256743.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 4		NP_001243672.1	Q5XKG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16	1	NM_007325.5	ENSP00000478489.1		P42263-2
GRIA3	ENST00000622768.5 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 16	5	NM_000828.5	ENSP00000481554.1		P42263-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183430

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000147

AC:

AN:

1090266

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

356216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26239

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19325

East Asian (EAS)

AF:

0.00

AC:

AN:

30179

South Asian (SAS)

AF:

0.00

AC:

AN:

53972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40521

Middle Eastern (MID)

AF:

0.000486

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

834931

Other (OTH)

AF:

0.0000874

AC:

AN:

45786

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.000223

Hom.:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jan 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects the initiator methionine of the GRIA3 mRNA. The next in-frame methionine is located at codon 7. This variant is present in population databases (rs752728469, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. ClinVar contains an entry for this variant (Variation ID: 624438). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 22, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 34426522, 28152038) -

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Pathogenic:1

Jul 07, 2014

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? pathogenic mutation (also known as c.2T>C), located in coding exon 1 of the GRIA3 gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the native initiation codon. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples with coverage at this position. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and possibly absence of protein translation. However, this amino acid position is not well conserved and a number of species do not have the initiation codon at this position. Furthermore, another ATG that is highly conserved among species is located down stream. The ATG sequence, located six amino acids down stream from the human reference sequence, is purported to function as the start site for rat GluR3 based on cDNA studies (Rampersad, V et al. Biochim Biophys Acta 1994;1219:563-6). In humans, iontropic flutamate receptors (iGluR) are purported to contain a short signal peptide (between 14-33 amino acids long) at the N-terminus that targets the protein to the cell membrane and mislocalization may disuprt neuronal function (Traynelis SF, Pharmacol. Rev. 2010 Sep; 62(3):405-96). It is anticipated that the p.M1? alteration, would result in the shortening of the signal peptide and lead to mislocalization of the hGluR3 protein; however direct evidence on this alteration's affect on transport to the cell membrane is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.079

T;T;T;T;T;.

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.90

.;D;D;D;.;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.60

D;D;D;D;D;D

MetaSVM

Benign

-1.1

PhyloP100

0.29

PROVEAN

Benign

-0.45

.;.;.;.;N;.

Sift

Pathogenic

0.0

.;.;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;D;.;D

Polyphen

0.0

.;B;.;.;B;B

Vest4

0.26

MutPred

0.96

Gain of phosphorylation at M1 (P = 0.0331);Gain of phosphorylation at M1 (P = 0.0331);Gain of phosphorylation at M1 (P = 0.0331);Gain of phosphorylation at M1 (P = 0.0331);Gain of phosphorylation at M1 (P = 0.0331);Gain of phosphorylation at M1 (P = 0.0331);

MVP

0.21

ClinPred

0.22

GERP RS

2.9

PromoterAI

0.0045

Neutral

(source)

Varity_R

0.62

gMVP

0.72

Mutation Taster

=132/68

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over