rs146022384

chrX-123403079-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.86

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]

ACMG classification

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: {Benign=2, Likely_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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 35 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.1166A>C	p.Lys389Thr	missense_variant	8/16	ENST00000622768.5
GRIA3	NM_007325.5	c.1166A>C	p.Lys389Thr	missense_variant	8/16	ENST00000620443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.1166A>C	p.Lys389Thr	missense_variant	8/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.1166A>C	p.Lys389Thr	missense_variant	8/16	5	NM_000828.5	A1
GRIA3	ENST00000620581.4	c.1166A>C	p.Lys389Thr	missense_variant, NMD_transcript_variant	8/17	1

Frequencies

GnomAD3 genomes AF: 0.000871 AC: 98 AN: 112496 Hom.: 0 Cov.: 23 AF XY: 0.00101 AC XY: 35 AN XY: 34660

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.: 0 AF XY: 0.000768 AC XY: 52 AN XY: 67734

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.: 2 Cov.: 20 AF XY: 0.000555 AC XY: 164 AN XY: 295625

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: 98 AN: 112551 Hom.: 0 Cov.: 23 AF XY: 0.00101 AC XY: 35 AN XY: 34725

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.: 50

Bravo AF: 0.000314

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.000873

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

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

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	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.56
MVP		0.94
ClinPred		0.020	T
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

Other links and lift over

dbSNP: rs146022384; hg19: chrX-122536930;