dbSNP rs10989563: GRIN3A:p.Asp835Tyr (chr9-101623429-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_133445.3(GRIN3A):c.2503G>T(p.Asp835Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GRIN3A
NM_133445.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

Genes affected

GRIN3A (HGNC:16767): (glutamate ionotropic receptor NMDA type subunit 3A) This gene encodes a subunit of the N-methyl-D-aspartate (NMDA) receptors, which belong to the superfamily of glutamate-regulated ion channels, and function in physiological and pathological processes in the central nervous system. This subunit shows greater than 90% identity to the corresponding subunit in rat. Studies in the knockout mouse deficient in this subunit suggest that this gene may be involved in the development of synaptic elements by modulating NMDA receptor activity. [provided by RefSeq, Jul 2008]

GRIN3A links:

ENSG00000299588 (HGNC:):

ENSG00000299588 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN3A	NM_133445.3 link	c.2503G>T	p.Asp835Tyr	missense_variant	Exon 5 of 9	ENST00000361820.6	NP_597702.2	Q8TCU5
GRIN3A	XM_011518211.3 link	c.2503G>T	p.Asp835Tyr	missense_variant	Exon 5 of 7		XP_011516513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRIN3A	ENST00000361820.6 link	c.2503G>T	p.Asp835Tyr	missense_variant	Exon 5 of 9	1	NM_133445.3	ENSP00000355155.3	Q8TCU5
ENSG00000299588	ENST00000764873.1 link	n.223+17054C>A		intron_variant	Intron 2 of 4
ENSG00000299588	ENST00000764875.1 link	n.198+17054C>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440114

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717888

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33022

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25972

East Asian (EAS)

AF:

0.00

AC:

AN:

39578

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092232

Other (OTH)

AF:

0.00

AC:

AN:

59662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

0.25

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.1

PhyloP100

7.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.53

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.83

MutPred

0.54

Loss of disorder (P = 0.0253);

MVP

0.64

MPC

0.65

ClinPred

0.99

GERP RS

5.7

Varity_R

0.65

gMVP

0.91

Mutation Taster

=39/61

disease causing

(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