X-123184599-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_000828.5(GRIA3):c.64C>T(p.Leu22Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,206,288 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L22I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000010 ( 0 hom. 1 hem. )

Consequence

GRIA3
NM_000828.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.05

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10588363).

BP6

Variant X-123184599-C-T is Benign according to our data. Variant chrX-123184599-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2907594.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000271 (3/110652) while in subpopulation EAS AF= 0.000867 (3/3459). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GRIA3	NM_000828.5 linkuse as main transcript	c.64C>T	p.Leu22Phe	missense_variant	1/16	ENST00000622768.5
GRIA3	NM_007325.5 linkuse as main transcript	c.64C>T	p.Leu22Phe	missense_variant	1/16	ENST00000620443.2
GRIA3	NM_001256743.2 linkuse as main transcript	c.64C>T	p.Leu22Phe	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2 linkuse as main transcript	c.64C>T	p.Leu22Phe	missense_variant	1/16	1	NM_007325.5	P4	P42263-2
GRIA3	ENST00000622768.5 linkuse as main transcript	c.64C>T	p.Leu22Phe	missense_variant	1/16	5	NM_000828.5	A1	P42263-1

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110604

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

32828

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000864

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:

0.0000382

AC:

AN:

183412

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000505

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:

0.0000100

AC:

AN:

1095636

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000364

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110652

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

32886

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000867

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.047

T;T;T;T;T;.

FATHMM_MKL

Uncertain

0.88

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.55

Sift4G

Benign

0.40

T;T;T;T;T;T

Polyphen

0.0050, 0.0080

.;B;.;.;B;B

Vest4

0.33

MutPred

0.47

Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);Loss of helix (P = 0.0444);

MVP

0.65

ClinPred

0.23

GERP RS

4.8

Varity_R

0.22

gMVP

0.48

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