8-143991546-C-T

Variant names:

• chr8-143991546-C-T
• rs1322266792
• NM_001009184.2:c.323C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001009184.2(GRINA):​c.323C>T​(p.Pro108Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,413,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GRINA NM_001009184.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.99

Genes affected

GRINA (HGNC:4589): (glutamate ionotropic receptor NMDA type subunit associated protein 1) Predicted to enable transmembrane transporter binding activity. Predicted to act upstream of or within endoplasmic reticulum calcium ion homeostasis and negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway. Predicted to be located in Golgi apparatus and endoplasmic reticulum. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

PARP10 (HGNC:25895): (poly(ADP-ribose) polymerase family member 10) Poly(ADP-ribose) polymerases (PARPs), such as PARP10, regulate gene transcription by altering chromatin organization by adding ADP-ribose to histones. PARPs can also function as transcriptional cofactors (Yu et al., 2005 [PubMed 15674325]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15551907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRINA	NM_001009184.2	c.323C>T	p.Pro108Leu	missense_variant	Exon 2 of 7	ENST00000395068.9	NP_001009184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRINA	ENST00000395068.9	c.323C>T	p.Pro108Leu	missense_variant	Exon 2 of 7	1	NM_001009184.2	ENSP00000378507.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1413332 Hom.: 0 Cov.: 26 AF XY: 0.00000142 AC XY: 1 AN XY: 704472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323C>T (p.P108L) alteration is located in exon 2 (coding exon 1) of the GRINA gene. This alteration results from a C to T substitution at nucleotide position 323, causing the proline (P) at amino acid position 108 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.085	T;T;T
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.056	B;.;B
Vest4		0.38
MutPred		0.27		Loss of glycosylation at P108 (P = 0.0057);Loss of glycosylation at P108 (P = 0.0057);Loss of glycosylation at P108 (P = 0.0057);
MVP		0.068
MPC		0.0074
ClinPred		0.91	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.35
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1322266792; hg19: chr8-145065714;