NM_000828.5:c.1200T>C

Variant names:

• chrX-123403426-T-C
• rs502434
• NM_000828.5:c.1200T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000828.5(GRIA3):​c.1200T>C​(p.Asn400Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (12338 hom., 18554 hem., cov: 23)
  • Exomes 𝑓: 0.59 (130711 hom. 197798 hem.)
  • Failed GnomAD Quality Control
• Consequence: GRIA3 NM_000828.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.14
• Publications: 20 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

ENSG00000307341 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-123403426-T-C is Benign according to our data. Variant chrX-123403426-T-C is described in ClinVar as Benign. ClinVar VariationId is 129167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.

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.1200T>C	p.Asn400Asn	synonymous	Exon 9 of 16	NP_000819.4	P42263-1
	GRIA3	NM_007325.5	MANE Select	c.1200T>C	p.Asn400Asn	synonymous	Exon 9 of 16	NP_015564.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIA3	ENST00000620443.2	TSL:1 MANE Select	c.1200T>C	p.Asn400Asn	synonymous	Exon 9 of 16	ENSP00000478489.1	P42263-2
	GRIA3	ENST00000622768.5	TSL:5 MANE Plus Clinical	c.1200T>C	p.Asn400Asn	synonymous	Exon 9 of 16	ENSP00000481554.1	P42263-1
	GRIA3	ENST00000620581.4	TSL:1	n.1200T>C		non_coding_transcript_exon	Exon 9 of 17	ENSP00000481875.1	A0A087WYJ6

Frequencies

GnomAD3 genomes AF: 0.559 AC: 61905 AN: 110644 Hom.: 12341 Cov.: 23

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.665

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.644

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.730

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.548

GnomAD2 exomes AF: 0.587 AC: 107501 AN: 183055 AF XY: 0.587

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.560

Gnomad ASJ exome AF: 0.638

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.737

Gnomad NFE exome AF: 0.612

Gnomad OTH exome AF: 0.602

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.594 AC: 630466 AN: 1061632 Hom.: 130711 Cov.: 27 AF XY: 0.585 AC XY: 197798 AN XY: 338076

African (AFR) AF: 0.439 AC: 11302 AN: 25766

American (AMR) AF: 0.559 AC: 19646 AN: 35138

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 12210 AN: 19087

East Asian (EAS) AF: 0.665 AC: 19969 AN: 30029

South Asian (SAS) AF: 0.461 AC: 24586 AN: 53368

European-Finnish (FIN) AF: 0.726 AC: 29414 AN: 40517

Middle Eastern (MID) AF: 0.607 AC: 2451 AN: 4038

European-Non Finnish (NFE) AF: 0.599 AC: 484820 AN: 808807

Other (OTH) AF: 0.581 AC: 26068 AN: 44882

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.559 AC: 61934 AN: 110702 Hom.: 12338 Cov.: 23 AF XY: 0.563 AC XY: 18554 AN XY: 32974

African (AFR) AF: 0.436 AC: 13276 AN: 30480

American (AMR) AF: 0.572 AC: 5972 AN: 10438

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 1690 AN: 2624

East Asian (EAS) AF: 0.636 AC: 2202 AN: 3463

South Asian (SAS) AF: 0.450 AC: 1168 AN: 2593

European-Finnish (FIN) AF: 0.730 AC: 4332 AN: 5936

Middle Eastern (MID) AF: 0.633 AC: 133 AN: 210

European-Non Finnish (NFE) AF: 0.604 AC: 31878 AN: 52777

Other (OTH) AF: 0.554 AC: 837 AN: 1510

Alfa AF: 0.574 Hom.: 44959

Bravo AF: 0.551

EpiCase AF: 0.608

EpiControl AF: 0.614

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Syndromic X-linked intellectual disability 94 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.3
DANN	Benign	0.72
PhyloP100		1.1
Mutation Taster		=95/5	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: rs502434; hg19: chrX-122537277; COSMIC: COSV52076814;