chr19-1000859-C-T

Position:

• chr19-1000859-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138690.3(GRIN3B):​c.422C>T​(p.Ala141Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000397 in 1,259,610 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.295

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096158266).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRIN3B	NM_138690.3	c.422C>T	p.Ala141Val	missense_variant	1/9	ENST00000234389.3	NP_619635.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRIN3B	ENST00000234389.3	c.422C>T	p.Ala141Val	missense_variant	1/9	1	NM_138690.3	ENSP00000234389	P1
	ENST00000588380.1	n.270-692G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000397 AC: 5 AN: 1259610 Hom.: 0 Cov.: 34 AF XY: 0.00000323 AC XY: 2 AN XY: 618964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000362

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000392

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2024

The c.422C>T (p.A141V) alteration is located in exon 1 (coding exon 1) of the GRIN3B gene. This alteration results from a C to T substitution at nucleotide position 422, causing the alanine (A) at amino acid position 141 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.92	L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.047
Sift	Benign	0.063	T
Sift4G	Benign	0.18	T
Polyphen		0.0040	B
Vest4		0.018
MutPred		0.40		Loss of disorder (P = 0.0573);
MVP		0.44
MPC		0.11
ClinPred		0.14	T
GERP RS		1.2
Varity_R		0.045
gMVP		0.32

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: rs2038678248; hg19: chr19-1000858;