chrX-123184549-A-C

Position:

chrX-123184549-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000828.5(GRIA3):c.14A>C(p.Lys5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,206,609 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000036 ( 0 hom. 2 hem. )

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.33

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19359592).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GRIA3	NM_000828.5 linkuse as main transcript	c.14A>C	p.Lys5Thr	missense_variant	1/16	ENST00000622768.5	NP_000819.4
GRIA3	NM_007325.5 linkuse as main transcript	c.14A>C	p.Lys5Thr	missense_variant	1/16	ENST00000620443.2	NP_015564.5
GRIA3	NM_001256743.2 linkuse as main transcript	c.14A>C	p.Lys5Thr	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.14A>C	p.Lys5Thr	missense_variant	1/16	1	NM_007325.5	ENSP00000478489	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.14A>C	p.Lys5Thr	missense_variant	1/16	5	NM_000828.5	ENSP00000481554	A1	P42263-1

Frequencies

GnomAD3 genomes

AF:

0.00000904

AC:

AN:

110579

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32807

show subpopulations

Gnomad AFR

AF:

0.0000330

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

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1096030

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

361464

show subpopulations

Gnomad4 AFR exome

AF:

0.000114

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:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000904

AC:

AN:

110579

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32807

show subpopulations

Gnomad4 AFR

AF:

0.0000330

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:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1429226). This variant has not been reported in the literature in individuals affected with GRIA3-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 5 of the GRIA3 protein (p.Lys5Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;T;T;T;T;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

.;D;D;D;.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N;.;.;N;N

MutationTaster

Benign

0.91

N;N;N;N;N;N

PrimateAI

Uncertain

0.66

Sift4G

Pathogenic

0.0

D;T;D;T;T;T

Polyphen

0.016, 0.027

.;B;.;.;B;B

Vest4

0.43

MutPred

0.28

Loss of methylation at K5 (P = 0.0067);Loss of methylation at K5 (P = 0.0067);Loss of methylation at K5 (P = 0.0067);Loss of methylation at K5 (P = 0.0067);Loss of methylation at K5 (P = 0.0067);Loss of methylation at K5 (P = 0.0067);

MVP

0.95

ClinPred

0.48

GERP RS

5.3

Varity_R

0.15

gMVP

0.42

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