19-1000786-C-T

Variant names:

• chr19-1000786-C-T
• rs12986002
• NM_138690.3:c.349C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 12/21 in silico tools predict 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.997
• Publications: 16 publications found

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]

ENSG00000266990 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1274762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138690.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN3B	NM_138690.3	MANE Select	c.349C>T	p.His117Tyr	missense	Exon 1 of 9	NP_619635.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN3B	ENST00000234389.3	TSL:1 MANE Select	c.349C>T	p.His117Tyr	missense	Exon 1 of 9	ENSP00000234389.3
	ENSG00000266990	ENST00000588380.1	TSL:5	n.270-619G>A		intron	N/A

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

GnomAD2 exomes AF: 0.419 AC: 24713 AN: 59028 AF XY: 0.405

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 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

African (AFR) AF: 0.279 AC: 7126 AN: 25564

American (AMR) AF: 0.427 AC: 8914 AN: 20896

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 8798 AN: 22236

East Asian (EAS) AF: 0.251 AC: 7000 AN: 27876

South Asian (SAS) AF: 0.285 AC: 19943 AN: 69972

European-Finnish (FIN) AF: 0.481 AC: 15484 AN: 32206

Middle Eastern (MID) AF: 0.337 AC: 1278 AN: 3796

European-Non Finnish (NFE) AF: 0.482 AC: 499995 AN: 1038314

Other (OTH) AF: 0.425 AC: 22638 AN: 53230

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

African (AFR) AF: 0.320 AC: 11799 AN: 36858

American (AMR) AF: 0.438 AC: 6267 AN: 14296

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1340 AN: 3260

East Asian (EAS) AF: 0.289 AC: 1345 AN: 4658

South Asian (SAS) AF: 0.293 AC: 1275 AN: 4348

European-Finnish (FIN) AF: 0.479 AC: 4864 AN: 10146

Middle Eastern (MID) AF: 0.381 AC: 106 AN: 278

European-Non Finnish (NFE) AF: 0.498 AC: 32298 AN: 64800

Other (OTH) AF: 0.418 AC: 815 AN: 1952

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.0
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
PromoterAI		-0.012	Neutral
Varity_R		0.12
gMVP		0.47
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: rs12986002; hg19: chr19-1000785; COSMIC: COSV52258462; COSMIC: COSV52258462;