11-88508785-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001143831.3(GRM5):c.3446A>C(p.Glu1149Ala) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRM5 NM_001143831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GRM5
• BP4: Computational evidence support a benign effect (MetaRNN=0.18886513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM5	NM_001143831.3	c.3446A>C	p.Glu1149Ala	missense_variant	10/10	ENST00000305447.5
GRM5-AS1	NR_049724.1	n.4210T>G		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM5	ENST00000305447.5	c.3446A>C	p.Glu1149Ala	missense_variant	10/10	1	NM_001143831.3	A2
GRM5	ENST00000305432.9	c.3350A>C	p.Glu1117Ala	missense_variant	8/8	1		P2
GRM5-AS1	ENST00000526448.1	n.4210T>G		non_coding_transcript_exon_variant	1/6	5
GRM5	ENST00000455756.6	c.3350A>C	p.Glu1117Ala	missense_variant	9/9	2		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Nov 15, 2021

The c.3446A>C (p.E1149A) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a A to C substitution at nucleotide position 3446, causing the glutamic acid (E) at amino acid position 1149 to be replaced by an alanine (A). 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	0.058
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	19
Dann	Benign	0.81
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.20
MutPred		0.18		.;.;Gain of stability (P = 0.0417);
MVP		0.31
ClinPred		0.16	T
GERP RS		3.0
Varity_R		0.088
gMVP		0.57

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: chr11-88241953;