11-88508707-G-A

Variant names:

• chr11-88508707-G-A
• NM_001143831.3:c.3524C>T

Variant summary

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

The NM_001143831.3(GRM5):​c.3524C>T​(p.Ser1175Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GRM5 NM_001143831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.49

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM5	NM_001143831.3	c.3524C>T	p.Ser1175Leu	missense_variant	Exon 10 of 10	ENST00000305447.5	NP_001137303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM5	ENST00000305447.5	c.3524C>T	p.Ser1175Leu	missense_variant	Exon 10 of 10	1	NM_001143831.3	ENSP00000306138.4
GRM5	ENST00000305432.9	c.3428C>T	p.Ser1143Leu	missense_variant	Exon 8 of 8	1		ENSP00000305905.5
GRM5	ENST00000455756.6	c.3428C>T	p.Ser1143Leu	missense_variant	Exon 9 of 9	2		ENSP00000405690.2
GRM5-AS1	ENST00000526448.1	n.4132G>A		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447722 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720366

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3524C>T (p.S1175L) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a C to T substitution at nucleotide position 3524, causing the serine (S) at amino acid position 1175 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	0.12
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Benign	1.1	.;.;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.62	P;P;B
Vest4		0.59
MutPred		0.41		.;.;Loss of glycosylation at S1175 (P = 0.0014);
MVP		0.80
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.65
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-88241875;