19-1000786-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_138690.3(GRIN3B):c.349C>T(p.His117Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,435,580 control chromosomes in the GnomAD database, including 151,015 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H117L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.43 (12864 hom., cov: 30)
  • Exomes 𝑓: 0.46 (138151 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.997

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.9942393E-4).
• BP6: Variant 19-1000786-C-T is Benign according to our data. Variant chr19-1000786-C-T is described in ClinVar as [Benign]. Clinvar id is 1274762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRIN3B	NM_138690.3	c.349C>T	p.His117Tyr	missense_variant	1/9	ENST00000234389.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRIN3B	ENST00000234389.3	c.349C>T	p.His117Tyr	missense_variant	1/9	1	NM_138690.3	P1
	ENST00000588380.1	n.270-619G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.429 AC: 60701 AN: 141380 Hom.: 12872 Cov.: 30

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.378

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.419 AC: 24713 AN: 59028 Hom.: 5462 AF XY: 0.405 AC XY: 14374 AN XY: 35488

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.443

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.313

Gnomad SAS exome AF: 0.290

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.457 AC: 591176 AN: 1294090 Hom.: 138151 Cov.: 40 AF XY: 0.452 AC XY: 288290 AN XY: 637648

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.427

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.285

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.482

Gnomad4 OTH exome AF: 0.425

GnomAD4 genome AF: 0.429 AC: 60697 AN: 141490 Hom.: 12864 Cov.: 30 AF XY: 0.425 AC XY: 29376 AN XY: 69128

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.293

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.498

Gnomad4 OTH AF: 0.418

Alfa AF: 0.433 Hom.: 1826

Bravo AF: 0.395

ExAC AF: 0.210 AC: 4833

Asia WGS AF: 0.261 AC: 897 AN: 3430

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.00030	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.096
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.015	D
Polyphen		0.54	P
Vest4		0.069
MPC		0.13
ClinPred		0.0031	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.47

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: rs12986002; hg19: chr19-1000785; COSMIC: COSV52258462; COSMIC: COSV52258462;