rs61740996

Variant names:

• chrX-123184550-G-A
• rs61740996
• NM_000828.5:c.15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007325.5(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_007325.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.56
• Publications: 0 publications found

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

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	NM_000828.5	MANE Plus Clinical	c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 16	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 16	NP_015564.5
	GRIA3	NM_001256743.2		c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 4	NP_001243672.1	Q5XKG2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 16	ENSP00000478489.1	P42263-2
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 16	ENSP00000481554.1	P42263-1
	GRIA3	ENST00000611689.4	TSL:1	c.15G>A	p.Lys5Lys	synonymous	Exon 1 of 4	ENSP00000478758.1	Q5XKG2

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1051 AN: 110660 Hom.: 17 Cov.: 21

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

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

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: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54093

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.000971 AC: 4 AN: 4118

European-Non Finnish (NFE) AF: 0.000117 AC: 98 AN: 840358

Other (OTH) AF: 0.00280 AC: 129 AN: 46029

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

African (AFR) AF: 0.0325 AC: 989 AN: 30394

American (AMR) AF: 0.00402 AC: 42 AN: 10447

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3479

South Asian (SAS) AF: 0.00 AC: 0 AN: 2547

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5859

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000227 AC: 12 AN: 52969

Other (OTH) AF: 0.00537 AC: 8 AN: 1490

Alfa AF: 0.0154 Hom.: 135

Bravo AF: 0.0114

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		6.6
PromoterAI		-0.055	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61740996; hg19: chrX-122318402;