11-88508809-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001143831.3(GRM5):c.3422G>A(p.Arg1141Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,521,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GRM5 NM_001143831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.447

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0649423).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM5	NM_001143831.3	c.3422G>A	p.Arg1141Gln	missense_variant	10/10	ENST00000305447.5
GRM5-AS1	NR_049724.1	n.4234C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM5	ENST00000305447.5	c.3422G>A	p.Arg1141Gln	missense_variant	10/10	1	NM_001143831.3	A2
GRM5	ENST00000305432.9	c.3326G>A	p.Arg1109Gln	missense_variant	8/8	1		P2
GRM5-AS1	ENST00000526448.1	n.4234C>T		non_coding_transcript_exon_variant	1/6	5
GRM5	ENST00000455756.6	c.3326G>A	p.Arg1109Gln	missense_variant	9/9	2		P2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151874 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000864 AC: 10 AN: 115676 Hom.: 0 AF XY: 0.0000939 AC XY: 6 AN XY: 63918

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000192

Gnomad OTH exome AF: 0.000313

GnomAD4 exome AF: 0.000166 AC: 228 AN: 1369978 Hom.: 0 Cov.: 30 AF XY: 0.000172 AC XY: 116 AN XY: 675456

Gnomad4 AFR exome AF: 0.000176

Gnomad4 AMR exome AF: 0.0000306

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: 0.000201

Gnomad4 OTH exome AF: 0.000123

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74172

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.0000575 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.3422G>A (p.R1141Q) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a G to A substitution at nucleotide position 3422, causing the arginine (R) at amino acid position 1141 to be replaced by a glutamine (Q). 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	0.085
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	3.2
Dann	Benign	0.90
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.53	T;.;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.065	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.10	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0040	B;B;B
Vest4		0.080
MutPred		0.084		.;.;Loss of helix (P = 0.2022);
MVP		0.27
ClinPred		0.021	T
GERP RS		-0.86
Varity_R		0.028
gMVP		0.20

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

LitVar

Other links and lift over

dbSNP: rs199656847; hg19: chr11-88241977;