rs139058646

Variant names:

• chrX-123417394-T-A
• rs139058646
• NM_000828.5:c.1501-8T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-123417394-T-A
• chrX-123417394-T-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000828.5(GRIA3):​c.1501-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00833 in 1,195,768 control chromosomes in the GnomAD database, including 38 homozygotes. There are 3,172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (4 hom., 303 hem., cov: 23)
  • Exomes 𝑓: 0.0084 (34 hom. 2869 hem.)
• Consequence: GRIA3 NM_000828.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002496
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.804
• 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: 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

ENSG00000307341 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-123417394-T-A is Benign according to our data. Variant chrX-123417394-T-A is described in ClinVar as Benign. ClinVar VariationId is 129168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000828.5. 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.1501-8T>A		splice_region intron	N/A	NP_000819.4
	GRIA3	NM_007325.5	MANE Select	c.1501-8T>A		splice_region intron	N/A	NP_015564.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.1501-8T>A		splice_region intron	N/A	ENSP00000478489.1
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.1501-8T>A		splice_region intron	N/A	ENSP00000481554.1
	GRIA3	ENST00000620581.4	TSL:1	n.1501-8T>A		splice_region intron	N/A	ENSP00000481875.1

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 880 AN: 112024 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.00120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00522

Gnomad FIN AF: 0.0315

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.0112

GnomAD2 exomes AF: 0.00832 AC: 1498 AN: 180082 AF XY: 0.00860

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.00245

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.00884

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00838 AC: 9080 AN: 1083695 Hom.: 34 Cov.: 27 AF XY: 0.00818 AC XY: 2869 AN XY: 350651

African (AFR) AF: 0.00142 AC: 37 AN: 26053

American (AMR) AF: 0.00626 AC: 219 AN: 34983

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 29 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 30127

South Asian (SAS) AF: 0.00746 AC: 398 AN: 53358

European-Finnish (FIN) AF: 0.0258 AC: 1044 AN: 40495

Middle Eastern (MID) AF: 0.0169 AC: 69 AN: 4090

European-Non Finnish (NFE) AF: 0.00838 AC: 6954 AN: 829682

Other (OTH) AF: 0.00723 AC: 330 AN: 45645

GnomAD4 genome AF: 0.00784 AC: 879 AN: 112073 Hom.: 4 Cov.: 23 AF XY: 0.00885 AC XY: 303 AN XY: 34243

African (AFR) AF: 0.00120 AC: 37 AN: 30907

American (AMR) AF: 0.0115 AC: 121 AN: 10561

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00561 AC: 15 AN: 2673

European-Finnish (FIN) AF: 0.0315 AC: 191 AN: 6072

Middle Eastern (MID) AF: 0.0415 AC: 9 AN: 217

European-Non Finnish (NFE) AF: 0.00914 AC: 486 AN: 53200

Other (OTH) AF: 0.0104 AC: 16 AN: 1535

Alfa AF: 0.00369 Hom.: 27

Bravo AF: 0.00637

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Syndromic X-linked intellectual disability 94 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.3
DANN	Benign	0.45
PhyloP100		0.80
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.014
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: rs139058646; hg19: chrX-122551245; COSMIC: COSV105859121;