11-88508855-C-A

Variant names:

• chr11-88508855-C-A
• rs1274525406
• NM_001143831.3:c.3376G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001143831.3(GRM5):​c.3376G>T​(p.Gly1126Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1126S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRM5 NM_001143831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

Genes affected

GRM5 (HGNC:4597): (glutamate metabotropic receptor 5) This gene encodes a member of the G-protein coupled receptor 3 protein family. The encoded protein is a metabatropic glutamate receptor, whose signaling activates a phosphatidylinositol-calcium second messenger system. This protein may be involved in the regulation of neural network activity and synaptic plasticity. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. A pseudogene of this gene has been defined on chromosome 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GRM5-AS1 (HGNC:40265): (GRM5 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37582028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143831.3. 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
	GRM5	NM_001143831.3	MANE Select	c.3376G>T	p.Gly1126Cys	missense	Exon 10 of 10	NP_001137303.1	P41594-1
	GRM5	NM_000842.5		c.3280G>T	p.Gly1094Cys	missense	Exon 9 of 9	NP_000833.1	P41594-2
	GRM5	NM_001384268.1		c.3280G>T	p.Gly1094Cys	missense	Exon 9 of 9	NP_001371197.1	P41594-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM5	ENST00000305447.5	TSL:1 MANE Select	c.3376G>T	p.Gly1126Cys	missense	Exon 10 of 10	ENSP00000306138.4	P41594-1
	GRM5	ENST00000305432.9	TSL:1	c.3280G>T	p.Gly1094Cys	missense	Exon 8 of 8	ENSP00000305905.5	P41594-2
	GRM5	ENST00000962224.1		c.3376G>T	p.Gly1126Cys	missense	Exon 10 of 10	ENSP00000632283.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000555 AC: 1 AN: 180192 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000423 AC: 6 AN: 1418334 Hom.: 0 Cov.: 30 AF XY: 0.00000569 AC XY: 4 AN XY: 702540

African (AFR) AF: 0.00 AC: 0 AN: 30960

American (AMR) AF: 0.00 AC: 0 AN: 38596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25084

East Asian (EAS) AF: 0.00 AC: 0 AN: 36572

South Asian (SAS) AF: 0.00 AC: 0 AN: 80590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000550 AC: 6 AN: 1091694

Other (OTH) AF: 0.00 AC: 0 AN: 58720

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.045
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.25
Sift	Uncertain	0.028	D
Sift4G	Benign	0.087	T
Polyphen		0.94	P
Vest4		0.27
MutPred		0.22		Loss of helix (P = 0.0237)
MVP		0.54
ClinPred		0.72	D
GERP RS		4.7
Varity_R		0.28
gMVP		0.49
Mutation Taster		=69/31	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: rs1274525406; hg19: chr11-88242023;