chrX-123184578-G-A

Position:

chrX-123184578-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000828.5(GRIA3):c.43G>A(p.Val15Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,207,995 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 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 0.00014 ( 0 hom., 4 hem., cov: 21)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.10

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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07741743).

BP6

Variant X-123184578-G-A is Benign according to our data. Variant chrX-123184578-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1708612.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000144 (16/110798) while in subpopulation AFR AF= 0.000526 (16/30390). AF 95% confidence interval is 0.00033. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRIA3	NM_000828.5 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	1/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	1/16	ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	1/4		NP_001243672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	1/16	1	NM_007325.5	ENSP00000478489	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.43G>A	p.Val15Ile	missense_variant	1/16	5	NM_000828.5	ENSP00000481554	A1	P42263-1

Frequencies

GnomAD3 genomes

AF:

0.000144

AC:

AN:

110798

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

33008

show subpopulations

Gnomad AFR

AF:

0.000526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183477

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67907

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097197

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362563

show subpopulations

Gnomad4 AFR exome

AF:

0.000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000144

AC:

AN:

110798

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

33008

show subpopulations

Gnomad4 AFR

AF:

0.000526

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 29, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.050

T;T;T;T;T;.

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.74

.;T;T;T;.;T

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.077

T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

.;N;.;.;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.39

Sift4G

Benign

0.32

T;T;T;T;T;T

Polyphen

0.010, 0.017

.;B;.;.;B;B

Vest4

0.14

MVP

0.53

ClinPred

0.074

GERP RS

3.3

Varity_R

0.052

gMVP

0.49

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