Genetic Variant GRIN3A:p.Arg480His (chr9-101670973-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_133445.3(GRIN3A):c.1439G>A(p.Arg480His) variant causes a missense change. The variant allele was found at a frequency of 0.0194 in 1,613,932 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 53 hom., cov: 33)

Exomes 𝑓: 0.020 ( 385 hom. )

Consequence

GRIN3A
NM_133445.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.08

Publications

15 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007731229).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2584/152220) while in subpopulation NFE AF = 0.0223 (1515/67992). AF 95% confidence interval is 0.0213. There are 53 homozygotes in GnomAd4. There are 1385 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133445.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN3A	NM_133445.3	MANE Select	c.1439G>A	p.Arg480His	missense	Exon 3 of 9	NP_597702.2	Q8TCU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRIN3A	ENST00000361820.6	TSL:1 MANE Select	c.1439G>A	p.Arg480His	missense	Exon 3 of 9	ENSP00000355155.3	Q8TCU5
ENSG00000299588	ENST00000764873.1		n.224-53775C>T		intron	N/A
ENSG00000299588	ENST00000764874.1		n.57+20420C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2583

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00386

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0104

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0615

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0223

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.0183

AC:

4594

AN:

251268

AF XY:

0.0186

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00648

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0612

Gnomad NFE exome

AF:

0.0232

Gnomad OTH exome

AF:

0.0181

GnomAD4 exome

AF:

0.0197

AC:

28795

AN:

1461712

Hom.:

385

Cov.:

AF XY:

0.0193

AC XY:

14055

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33468

American (AMR)

AF:

0.00707

AC:

316

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0122

AC:

318

AN:

26132

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.00380

AC:

328

AN:

86258

European-Finnish (FIN)

AF:

0.0592

AC:

3161

AN:

53420

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0212

AC:

23561

AN:

1111864

Other (OTH)

AF:

0.0164

AC:

992

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1552

3103

4655

6206

7758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

810

1620

2430

3240

4050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0170

AC:

2584

AN:

152220

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1385

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00385

AC:

160

AN:

41550

American (AMR)

AF:

0.0103

AC:

158

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00352

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0615

AC:

653

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0223

AC:

1515

AN:

67992

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

266

400

533

666

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0198

Hom.:

108

Bravo

AF:

0.0126

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0213

AC:

183

ExAC

AF:

0.0183

AC:

2223

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0189

EpiControl

AF:

0.0174

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0077

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.6

PhyloP100

4.1

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.44

Sift

Uncertain

0.018

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.27

MPC

0.64

ClinPred

0.018

GERP RS

5.8

Varity_R

0.11

gMVP

0.60

Mutation Taster

=69/31

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over