X-123253431-G-A

Position:

chrX-123253431-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000620443.2(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. 12/18 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
ENST00000620443.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.88

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 id is 281521.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000787 (88/111817) while in subpopulation AFR AF= 0.00263 (81/30789). AF 95% confidence interval is 0.00217. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant	3/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant	3/16	ENST00000620443.2	NP_015564.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant	3/16	1	NM_007325.5	ENSP00000478489	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant	3/16	5	NM_000828.5	ENSP00000481554	A1	P42263-1
GRIA3	ENST00000620581.4 linkuse as main transcript	c.397G>A	p.Ala133Thr	missense_variant, NMD_transcript_variant	3/17	1		ENSP00000481875
GRIA3	ENST00000479118.1 linkuse as main transcript	n.373G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.000787

AC:

AN:

111762

Hom.:

Cov.:

AF XY:

0.000884

AC XY:

AN XY:

33934

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

GnomAD3 exomes

AF:

0.000349

AC:

AN:

183345

Hom.:

AF XY:

0.000295

AC XY:

AN XY:

67809

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 SAS exome

AF:

0.000996

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

Gnomad4 AFR exome

AF:

0.00201

Gnomad4 AMR exome

AF:

0.000142

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.000997

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000499

Gnomad4 OTH exome

AF:

0.000304

GnomAD4 genome

AF:

0.000787

AC:

AN:

111817

Hom.:

Cov.:

AF XY:

0.000882

AC XY:

AN XY:

33999

show subpopulations

Gnomad4 AFR

AF:

0.00263

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000378

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00132

Alfa

AF:

0.000252

Hom.:

Bravo

AF:

0.000827

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000387

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

History of neurodevelopmental disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2013

There is insufficient or conflicting evidence for classification of this alteration. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;T;T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;.;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.0088

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

-1.0

N;.;N;N

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.79

REVEL

Benign

0.29

Sift4G

Benign

0.93

T;T;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.067

MVP

0.70

ClinPred

0.012

GERP RS

5.5

Varity_R

0.20

gMVP

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over