chrX-123184599-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_ModerateBP6_Moderate

The NM_007325.5(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_007325.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.05

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability 94
Inheritance: XL Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
X-linked intellectual disability due to GRIA3 anomalies
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GRIA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to X-linked complex neurodevelopmental disorder, syndromic X-linked intellectual disability 94, X-linked intellectual disability due to GRIA3 anomalies.

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 VariationId is 2907594.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007325.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIA3	NM_000828.5	MANE Plus Clinical	c.64C>T	p.Leu22Phe	missense	Exon 1 of 16	NP_000819.4	P42263-1
GRIA3	NM_007325.5	MANE Select	c.64C>T	p.Leu22Phe	missense	Exon 1 of 16	NP_015564.5
GRIA3	NM_001256743.2		c.64C>T	p.Leu22Phe	missense	Exon 1 of 4	NP_001243672.1	Q5XKG2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.64C>T	p.Leu22Phe	missense	Exon 1 of 16	ENSP00000478489.1	P42263-2
GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.64C>T	p.Leu22Phe	missense	Exon 1 of 16	ENSP00000481554.1	P42263-1
GRIA3	ENST00000611689.4	TSL:1	c.64C>T	p.Leu22Phe	missense	Exon 1 of 4	ENSP00000478758.1	Q5XKG2

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110604

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000382

AC:

AN:

183412

AF XY:

0.0000295

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 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

African (AFR)

AF:

0.00

AC:

AN:

26351

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.000364

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54087

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839862

Other (OTH)

AF:

0.00

AC:

AN:

46005

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110652

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

32886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30370

American (AMR)

AF:

0.00

AC:

AN:

10458

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.000867

AC:

AN:

3459

South Asian (SAS)

AF:

0.00

AC:

AN:

2526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5911

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52919

Other (OTH)

AF:

0.00

AC:

AN:

1483

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.700

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.047

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.32

PhyloP100

5.1

PrimateAI

Uncertain

0.55

Sift4G

Benign

0.40

Polyphen

0.0050

Vest4

0.33

MutPred

0.47

Loss of helix (P = 0.0444)

MVP

0.65

ClinPred

0.23

GERP RS

4.8

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.22

gMVP

0.48

Mutation Taster

=66/34

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over