chr19-1000786-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138690.3(GRIN3B):​c.349C>A​(p.His117Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,294,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H117Y) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: GRIN3B NM_138690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.997
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16349751).

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>A	p.His117Asn	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>A	p.His117Asn	missense	Exon 1 of 9	ENSP00000234389.3
	ENSG00000266990	ENST00000588380.1	TSL:5	n.270-619G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1294624 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 637968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25568

American (AMR) AF: 0.00 AC: 0 AN: 20932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22250

East Asian (EAS) AF: 0.00 AC: 0 AN: 27884

South Asian (SAS) AF: 0.0000143 AC: 1 AN: 70048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1038670

Other (OTH) AF: 0.00 AC: 0 AN: 53258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.067
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.056	T
Polyphen		0.072	B
Vest4		0.20
MutPred		0.43		Gain of catalytic residue at H117 (P = 0.0231)
MVP		0.29
MPC		0.15
ClinPred		0.22	T
GERP RS		2.5
PromoterAI		-0.033	Neutral
Varity_R		0.16
gMVP		0.42
Mutation Taster		=95/5	polymorphism

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;