dbSNP rs12986002: GRIN3B:p.His117Asn (chr19-1000786-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.997

Publications

0 publications found

Variant links:

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]

GRIN3B links:

ENSG00000266990 (HGNC:):

ENSG00000266990 links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN3B	NM_138690.3 link	c.349C>A	p.His117Asn	missense_variant	Exon 1 of 9	ENST00000234389.3	NP_619635.1	O60391Q5F0I5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN3B	ENST00000234389.3 link	c.349C>A	p.His117Asn	missense_variant	Exon 1 of 9	1	NM_138690.3	ENSP00000234389.3		O60391
ENSG00000266990	ENST00000588380.1 link	n.270-619G>T		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.72e-7

AC:

AN:

1294624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

637968

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

25568

American (AMR)

AF:

0.00

AC:

AN:

20932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22250

East Asian (EAS)

AF:

0.00

AC:

AN:

27884

South Asian (SAS)

AF:

0.0000143

AC:

AN:

70048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3796

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1038670

Other (OTH)

AF:

0.00

AC:

AN:

53258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.055

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.39

REVEL

Benign

0.067

Sift

Uncertain

0.019

Sift4G

Uncertain

0.056

Polyphen

0.072

Vest4

0.20

MutPred

0.43

Gain of catalytic residue at H117 (P = 0.0231);

MVP

0.29

MPC

0.15

ClinPred

0.22

GERP RS

2.5

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.16

gMVP

0.42

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over