NM_133445.3:c.3085T>C

Variant names:

• chr9-101573437-A-G
• rs75201933
• NM_133445.3:c.3085T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_133445.3(GRIN3A):​c.3085T>C​(p.Phe1029Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,614,028 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: GRIN3A NM_133445.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.50
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003691256).
• BP6: Variant 9-101573437-A-G is Benign according to our data. Variant chr9-101573437-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 773510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 19 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.3085T>C	p.Phe1029Leu	missense	Exon 9 of 9	NP_597702.2	Q8TCU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRIN3A	ENST00000361820.6	TSL:1 MANE Select	c.3085T>C	p.Phe1029Leu	missense	Exon 9 of 9	ENSP00000355155.3	Q8TCU5

Frequencies

GnomAD3 genomes AF: 0.00220 AC: 335 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00214 AC: 538 AN: 250980 AF XY: 0.00217

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00371

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00404 AC: 5904 AN: 1461794 Hom.: 19 Cov.: 32 AF XY: 0.00384 AC XY: 2792 AN XY: 727190

African (AFR) AF: 0.000568 AC: 19 AN: 33468

American (AMR) AF: 0.00145 AC: 65 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00178 AC: 95 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00497 AC: 5522 AN: 1111946

Other (OTH) AF: 0.00328 AC: 198 AN: 60392

GnomAD4 genome AF: 0.00220 AC: 335 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74430

African (AFR) AF: 0.000939 AC: 39 AN: 41530

American (AMR) AF: 0.00105 AC: 16 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00378 AC: 257 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00220 AC: 267

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00367

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.099
Sift	Benign	0.25	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.031
MutPred		0.26		Loss of catalytic residue at F1029 (P = 0.0772)
MVP		0.39
MPC		0.15
ClinPred		0.015	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.24
Mutation Taster		=87/13	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: rs75201933; hg19: chr9-104335719;