rs146022384

Positions:

chrX-123403079-A-C

Variant summary

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

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

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=0.011986196).

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 id is 493545.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chrX-123403079-A-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000871 (98/112551) while in subpopulation NFE AF= 0.00133 (71/53276). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIA3	NM_000828.5 linkuse as main transcript	c.1166A>C	p.Lys389Thr	missense_variant	8/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 linkuse as main transcript	c.1166A>C	p.Lys389Thr	missense_variant	8/16	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.1166A>C	p.Lys389Thr	missense_variant	8/16	1	NM_007325.5	ENSP00000478489	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.1166A>C	p.Lys389Thr	missense_variant	8/16	5	NM_000828.5	ENSP00000481554	A1	P42263-1
GRIA3	ENST00000620581.4 linkuse as main transcript	c.1166A>C	p.Lys389Thr	missense_variant, NMD_transcript_variant	8/17	1		ENSP00000481875

Frequencies

GnomAD3 genomes

AF:

0.000871

AC:

AN:

112496

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

34660

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

GnomAD3 exomes

AF:

0.000791

AC:

145

AN:

183214

Hom.:

AF XY:

0.000768

AC XY:

AN XY:

67734

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00394

Gnomad4 NFE exome

AF:

0.000465

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000871

AC:

AN:

112551

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

34725

show subpopulations

Gnomad4 AFR

AF:

0.0000322

Gnomad4 AMR

AF:

0.0000942

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00387

Gnomad4 NFE

AF:

0.00133

Gnomad4 OTH

AF:

0.000654

Alfa

AF:

0.00101

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2017

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;T;T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;.;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.80

REVEL

Benign

0.13

Sift4G

Benign

0.53

T;T;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.56

MVP

0.94

ClinPred

0.020

GERP RS

5.7

Varity_R

0.31

gMVP

0.79

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