19-1003173-C-T

Variant summary

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

The NM_138690.3(GRIN3B):c.470C>T(p.Thr157Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,494,280 control chromosomes in the GnomAD database, including 21,279 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1998 hom., cov: 34)
  • Exomes 𝑓: 0.16 (19281 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230

Genes affected

GRIN3B (HGNC:16768): (glutamate ionotropic receptor NMDA type subunit 3B) The protein encoded by this gene is a subunit of an N-methyl-D-aspartate (NMDA) receptor. The encoded protein is found primarily in motor neurons, where it forms a heterotetramer with GRIN1 to create an excitatory glycine receptor. Variations in this gene have been proposed to be linked to schizophrenia. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001303792).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN3B	NM_138690.3	c.470C>T	p.Thr157Met	missense_variant	2/9	ENST00000234389.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN3B	ENST00000234389.3	c.470C>T	p.Thr157Met	missense_variant	2/9	1	NM_138690.3	P1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20448 AN: 152124 Hom.: 2000 Cov.: 34

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.189 AC: 24052 AN: 127250 Hom.: 3057 AF XY: 0.181 AC XY: 12711 AN XY: 70216

Gnomad AFR exome AF: 0.0242

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.165

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.160 AC: 214664 AN: 1342036 Hom.: 19281 Cov.: 34 AF XY: 0.159 AC XY: 104691 AN XY: 657204

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.305

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.419

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.134 AC: 20441 AN: 152244 Hom.: 1998 Cov.: 34 AF XY: 0.137 AC XY: 10188 AN XY: 74424

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.123

Alfa AF: 0.151 Hom.: 2845

Bravo AF: 0.139

TwinsUK AF: 0.159 AC: 591

ALSPAC AF: 0.148 AC: 572

ESP6500AA AF: 0.0284 AC: 120

ESP6500EA AF: 0.138 AC: 1154

ExAC AF: 0.164 AC: 19336

Asia WGS AF: 0.270 AC: 935 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.049
Sift	Benign	0.093	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.16
MPC		0.24
ClinPred		0.014	T
GERP RS		3.4
Varity_R		0.050
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2240154; hg19: chr19-1003172; COSMIC: COSV52258834; COSMIC: COSV52258834;