rs75981117

chr9-101670766-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_133445.3(GRIN3A):c.1646A>G(p.Asn549Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00428 in 1,614,092 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (13 hom.)
• Consequence: GRIN3A NM_133445.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89

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 Likely_benign. Variant got -6 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity NMD3A_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.011829108).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN3A	NM_133445.3	c.1646A>G	p.Asn549Ser	missense_variant	3/9	ENST00000361820.6
GRIN3A	XM_011518211.3	c.1646A>G	p.Asn549Ser	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN3A	ENST00000361820.6	c.1646A>G	p.Asn549Ser	missense_variant	3/9	1	NM_133445.3	P1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152212 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00467

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00285 AC: 716 AN: 251128 Hom.: 1 AF XY: 0.00290 AC XY: 393 AN XY: 135714

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00454

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00443 AC: 6478 AN: 1461762 Hom.: 13 Cov.: 37 AF XY: 0.00435 AC XY: 3165 AN XY: 727194

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000568

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74496

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00458 Hom.: 1

Bravo AF: 0.00311

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00285 AC: 346

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00492

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.097
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.013	D
Polyphen		0.28	B
Vest4		0.61
MVP		0.58
MPC		0.12
ClinPred		0.040	T
GERP RS		4.6
Varity_R		0.21
gMVP		0.59

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: rs75981117; hg19: chr9-104433048;