9-101573400-C-T

Variant names:

• chr9-101573400-C-T
• rs3739722
• NM_133445.3:c.3122G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 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
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GRIN3A	NM_133445.3	c.3122G>A	p.Arg1041Gln	missense_variant	Exon 9 of 9	ENST00000361820.6	NP_597702.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN3A	ENST00000361820.6	c.3122G>A	p.Arg1041Gln	missense_variant	Exon 9 of 9	1	NM_133445.3	ENSP00000355155.3

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

GnomAD2 exomes AF: 0.140 AC: 35090 AN: 250962 AF XY: 0.135

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 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

African (AFR) AF: 0.213 AC: 7119 AN: 33470

American (AMR) AF: 0.177 AC: 7922 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 2011 AN: 26132

East Asian (EAS) AF: 0.221 AC: 8756 AN: 39694

South Asian (SAS) AF: 0.117 AC: 10053 AN: 86248

European-Finnish (FIN) AF: 0.0978 AC: 5224 AN: 53418

Middle Eastern (MID) AF: 0.113 AC: 653 AN: 5768

European-Non Finnish (NFE) AF: 0.129 AC: 142983 AN: 1111906

Other (OTH) AF: 0.132 AC: 7990 AN: 60386

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

African (AFR) AF: 0.211 AC: 8756 AN: 41470

American (AMR) AF: 0.155 AC: 2371 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0703 AC: 244 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1203 AN: 5142

South Asian (SAS) AF: 0.124 AC: 595 AN: 4814

European-Finnish (FIN) AF: 0.0929 AC: 982 AN: 10570

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.124 AC: 8417 AN: 67978

Other (OTH) AF: 0.146 AC: 307 AN: 2104

Alfa AF: 0.136 Hom.: 5133

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
PhyloP100		-2.0
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
Mutation Taster		=98/2	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: rs3739722; hg19: chr9-104335682; COSMIC: COSV62450795;