rs61740996

chrX-123184550-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000828.5(GRIA3):c.15G>A(p.Lys5=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.56

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 -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.15G>A	p.Lys5=	synonymous_variant	1/16	ENST00000622768.5
GRIA3	NM_007325.5	c.15G>A	p.Lys5=	synonymous_variant	1/16	ENST00000620443.2
GRIA3	NM_001256743.2	c.15G>A	p.Lys5=	synonymous_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.15G>A	p.Lys5=	synonymous_variant	1/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.15G>A	p.Lys5=	synonymous_variant	1/16	5	NM_000828.5	A1

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1051 AN: 110660 Hom.: 17 Cov.: 21 AF XY: 0.00801 AC XY: 263 AN XY: 32842

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

GnomAD3 exomes AF: 0.00271 AC: 497 AN: 183499 Hom.: 7 AF XY: 0.00200 AC XY: 136 AN XY: 67931

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 SAS exome AF: 0.0000524

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.: 14 Cov.: 29 AF XY: 0.000934 AC XY: 338 AN XY: 361712

Gnomad4 AFR exome AF: 0.0351

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.00950 AC: 1052 AN: 110714 Hom.: 17 Cov.: 21 AF XY: 0.00799 AC XY: 263 AN XY: 32906

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00402

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000227

Gnomad4 OTH AF: 0.00537

Alfa AF: 0.00504 Hom.: 25

Bravo AF: 0.0114

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 29, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2015

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	14
Dann	Benign	0.62

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: rs61740996; hg19: chrX-122318402;