X-123184519-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000828.5(GRIA3):c.-17T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000312 in 1,161,975 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 137 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., 6 hem., cov: 21)
  • Exomes 𝑓: 0.00032 (0 hom. 131 hem.)
• Consequence: GRIA3 NM_000828.5 5_prime_UTR
• Scores: Splicing: ADA: 0.01408
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant X-123184519-T-C is Benign according to our data. Variant chrX-123184519-T-C is described in ClinVar as [Benign]. Clinvar id is 1258859.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000235 (26/110433) while in subpopulation SAS AF= 0.000793 (2/2521). AF 95% confidence interval is 0.000265. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIA3	NM_000828.5	c.-17T>C		5_prime_UTR_variant	1/16	ENST00000622768.5
GRIA3	NM_007325.5	c.-17T>C		5_prime_UTR_variant	1/16	ENST00000620443.2
GRIA3	NM_001256743.2	c.-17T>C		5_prime_UTR_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIA3	ENST00000620443.2	c.-17T>C		5_prime_UTR_variant	1/16	1	NM_007325.5	P4
GRIA3	ENST00000622768.5	c.-17T>C		5_prime_UTR_variant	1/16	5	NM_000828.5	A1

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 26 AN: 110381 Hom.: 0 Cov.: 21 AF XY: 0.000184 AC XY: 6 AN XY: 32629

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000963

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000791

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00427

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000487 AC: 79 AN: 162269 Hom.: 0 AF XY: 0.000678 AC XY: 37 AN XY: 54539

Gnomad AFR exome AF: 0.0000817

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000627

Gnomad OTH exome AF: 0.000767

GnomAD4 exome AF: 0.000320 AC: 337 AN: 1051542 Hom.: 0 Cov.: 25 AF XY: 0.000400 AC XY: 131 AN XY: 327206

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.000210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000449

GnomAD4 genome AF: 0.000235 AC: 26 AN: 110433 Hom.: 0 Cov.: 21 AF XY: 0.000184 AC XY: 6 AN XY: 32691

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000961

Gnomad4 ASJ AF: 0.000380

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000793

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000479 Hom.: 1

Bravo AF: 0.000249

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.15
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: rs374449092; hg19: chrX-122318372;