9-101573400-C-T

Position:

• chr9-101573400-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133445.3(GRIN3A):​c.3122G>A​(p.Arg1041Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,613,756 control chromosomes in the GnomAD database, including 15,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1964 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13403 hom.)
• Consequence: GRIN3A NM_133445.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97

Genes affected

GRIN3A (HGNC:16767): (glutamate ionotropic receptor NMDA type subunit 3A) This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptors, which belong to the superfamily of glutamate-regulated ion channels, and function in physiological and pathological processes in the central nervous system. This subunit shows greater than 90% identity to the corresponding subunit in rat. Studies in the knockout mouse deficient in this subunit suggest that this gene may be involved in the development of synaptic elements by modulating NMDA receptor activity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044493973).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN3A	NM_133445.3	c.3122G>A	p.Arg1041Gln	missense_variant	9/9	ENST00000361820.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN3A	ENST00000361820.6	c.3122G>A	p.Arg1041Gln	missense_variant	9/9	1	NM_133445.3	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23011 AN: 151894 Hom.: 1964 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.140 AC: 35090 AN: 250962 Hom.: 2712 AF XY: 0.135 AC XY: 18284 AN XY: 135604

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.0756

Gnomad EAS exome AF: 0.232

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0955

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.132 AC: 192711 AN: 1461742 Hom.: 13403 Cov.: 33 AF XY: 0.131 AC XY: 95099 AN XY: 727170

Gnomad4 AFR exome AF: 0.213

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.0770

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.0978

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.152 AC: 23032 AN: 152014 Hom.: 1964 Cov.: 32 AF XY: 0.149 AC XY: 11050 AN XY: 74310

Gnomad4 AFR AF: 0.211

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0929

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.146

Alfa AF: 0.131 Hom.: 3523

Bravo AF: 0.161

TwinsUK AF: 0.129 AC: 479

ALSPAC AF: 0.132 AC: 508

ESP6500AA AF: 0.212 AC: 933

ESP6500EA AF: 0.131 AC: 1126

ExAC AF: 0.140 AC: 17037

Asia WGS AF: 0.191 AC: 661 AN: 3478

EpiCase AF: 0.121

EpiControl AF: 0.124

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.92
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.060
Sift	Benign	0.47	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.14
ClinPred		0.0026	T
GERP RS		-4.0
Varity_R		0.029
gMVP		0.11

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: rs3739722; hg19: chr9-104335682; COSMIC: COSV62450795;