chr19-1004741-T-C

Variant names:

• chr19-1004741-T-C
• rs2240157
• NM_138690.3:c.1240T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138690.3(GRIN3B):​c.1240T>C​(p.Trp414Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,607,864 control chromosomes in the GnomAD database, including 403,326 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (39300 hom., cov: 34)
  • Exomes 𝑓: 0.70 (364026 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 29 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9714284E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN3B	NM_138690.3	c.1240T>C	p.Trp414Arg	missense_variant	Exon 3 of 9	ENST00000234389.3	NP_619635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN3B	ENST00000234389.3	c.1240T>C	p.Trp414Arg	missense_variant	Exon 3 of 9	1	NM_138690.3	ENSP00000234389.3
GRIN3B	ENST00000588335.1	n.51-61T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108787 AN: 151976 Hom.: 39250 Cov.: 34

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.758

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.709

Gnomad OTH AF: 0.738

GnomAD2 exomes AF: 0.680 AC: 165352 AN: 243026 AF XY: 0.688

Gnomad AFR exome AF: 0.786

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.798

Gnomad EAS exome AF: 0.492

Gnomad FIN exome AF: 0.700

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.705 AC: 1026228 AN: 1455768 Hom.: 364026 Cov.: 63 AF XY: 0.707 AC XY: 511438 AN XY: 723454

African (AFR) AF: 0.794 AC: 26470 AN: 33356

American (AMR) AF: 0.534 AC: 23722 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.799 AC: 20725 AN: 25940

East Asian (EAS) AF: 0.531 AC: 21017 AN: 39550

South Asian (SAS) AF: 0.742 AC: 63799 AN: 85968

European-Finnish (FIN) AF: 0.705 AC: 36768 AN: 52170

Middle Eastern (MID) AF: 0.820 AC: 4721 AN: 5756

European-Non Finnish (NFE) AF: 0.709 AC: 786336 AN: 1108560

Other (OTH) AF: 0.710 AC: 42670 AN: 60072

GnomAD4 genome AF: 0.716 AC: 108891 AN: 152096 Hom.: 39300 Cov.: 34 AF XY: 0.713 AC XY: 52991 AN XY: 74346

African (AFR) AF: 0.790 AC: 32791 AN: 41522

American (AMR) AF: 0.593 AC: 9073 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2787 AN: 3472

East Asian (EAS) AF: 0.512 AC: 2630 AN: 5136

South Asian (SAS) AF: 0.760 AC: 3669 AN: 4830

European-Finnish (FIN) AF: 0.692 AC: 7324 AN: 10588

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.709 AC: 48149 AN: 67932

Other (OTH) AF: 0.742 AC: 1568 AN: 2114

Alfa AF: 0.705 Hom.: 55398

Bravo AF: 0.709

TwinsUK AF: 0.705 AC: 2613

ALSPAC AF: 0.715 AC: 2755

ESP6500AA AF: 0.786 AC: 3447

ESP6500EA AF: 0.712 AC: 6108

ExAC AF: 0.686 AC: 82899

Asia WGS AF: 0.658 AC: 2292 AN: 3478

EpiCase AF: 0.720

EpiControl AF: 0.729

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.1
DANN	Benign	0.44
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.049	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.6	N
PhyloP100		1.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	3.2	N
REVEL	Benign	0.067
Sift	Benign	0.39	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.022
MutPred		0.28		Gain of disorder (P = 0.0016);
MPC		0.20
ClinPred		0.012	T
GERP RS		3.4
Varity_R		0.043
gMVP		0.41
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2240157; hg19: chr19-1004740; COSMIC: COSV52260707; COSMIC: COSV52260707;