chrX-123184550-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000828.5(GRIA3):c.15G>A(p.Lys5Lys) variant causes a synonymous change. The variant allele was found at a frequency of 0.00192 in 1,206,984 control chromosomes in the GnomAD database, including 31 homozygotes. There are 601 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 17 hom., 263 hem., cov: 21)

Exomes 𝑓: 0.0012 ( 14 hom. 338 hem. )

Consequence

GRIA3
NM_000828.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.56

Publications

0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant X-123184550-G-A is Benign according to our data. Variant chrX-123184550-G-A is described in ClinVar as Benign. ClinVar VariationId is 129166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0095 (1052/110714) while in subpopulation AFR AF = 0.0325 (989/30394). AF 95% confidence interval is 0.0309. There are 17 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIA3	NM_000828.5 link	c.15G>A	p.Lys5Lys	synonymous_variant	Exon 1 of 16	ENST00000622768.5	NP_000819.4	P42263-1Q17R51
GRIA3	NM_007325.5 link	c.15G>A	p.Lys5Lys	synonymous_variant	Exon 1 of 16	ENST00000620443.2	NP_015564.5	P42263-2Q17R51
GRIA3	NM_001256743.2 link	c.15G>A	p.Lys5Lys	synonymous_variant	Exon 1 of 4		NP_001243672.1	Q5XKG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIA3	ENST00000620443.2 link	c.15G>A	p.Lys5Lys	synonymous_variant	Exon 1 of 16	1	NM_007325.5	ENSP00000478489.1		P42263-2
GRIA3	ENST00000622768.5 link	c.15G>A	p.Lys5Lys	synonymous_variant	Exon 1 of 16	5	NM_000828.5	ENSP00000481554.1		P42263-1

Frequencies

GnomAD3 genomes

AF:

0.00950

AC:

1051

AN:

110660

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00403

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.000227

Gnomad OTH

AF:

0.00544

GnomAD2 exomes

AF:

0.00271

AC:

497

AN:

183499

AF XY:

0.00200

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00154

GnomAD4 exome

AF:

0.00115

AC:

1265

AN:

1096270

Hom.:

Cov.:

AF XY:

0.000934

AC XY:

338

AN XY:

361712

show subpopulations

African (AFR)

AF:

0.0351

AC:

924

AN:

26357

American (AMR)

AF:

0.00295

AC:

104

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19377

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.000111

AC:

AN:

54093

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.000971

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.000117

AC:

AN:

840358

Other (OTH)

AF:

0.00280

AC:

129

AN:

46029

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00950

AC:

1052

AN:

110714

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

263

AN XY:

32906

show subpopulations

African (AFR)

AF:

0.0325

AC:

989

AN:

30394

American (AMR)

AF:

0.00402

AC:

AN:

10447

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3479

South Asian (SAS)

AF:

0.00

AC:

AN:

2547

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5859

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000227

AC:

AN:

52969

Other (OTH)

AF:

0.00537

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

109

145

181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0154

Hom.:

135

Bravo

AF:

0.0114

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Mar 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases

Benign:1

Nov 09, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.62

PhyloP100

6.6

PromoterAI

-0.055

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over