11-88509167-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001143831.3(GRM5):c.3064A>G(p.Ile1022Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000481 in 1,537,034 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 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: GRM5 NM_001143831.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM5
• BP4: Computational evidence support a benign effect (MetaRNN=0.073340654).
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM5	NM_001143831.3	c.3064A>G	p.Ile1022Val	missense_variant	10/10	ENST00000305447.5
GRM5-AS1	NR_049724.1	n.4364+228T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM5	ENST00000305447.5	c.3064A>G	p.Ile1022Val	missense_variant	10/10	1	NM_001143831.3	A2
GRM5	ENST00000305432.9	c.2968A>G	p.Ile990Val	missense_variant	8/8	1		P2
GRM5-AS1	ENST00000526448.1	n.4364+228T>C		intron_variant, non_coding_transcript_variant		5
GRM5	ENST00000455756.6	c.2968A>G	p.Ile990Val	missense_variant	9/9	2		P2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151886 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000609 AC: 8 AN: 131290 Hom.: 0 AF XY: 0.0000975 AC XY: 7 AN XY: 71766

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 SAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000421

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000484 AC: 67 AN: 1385040 Hom.: 0 Cov.: 34 AF XY: 0.0000732 AC XY: 50 AN XY: 683086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000471

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000260

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74304

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000529

ExAC AF: 0.0000187 AC: 1

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

Jan 05, 2022

The c.3064A>G (p.I1022V) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a A to G substitution at nucleotide position 3064, causing the isoleucine (I) at amino acid position 1022 to be replaced by a valine (V). 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	Benign	-0.28	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.75
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;.;T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.80	T;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0080	B;B;B
Vest4		0.080
MutPred		0.085		.;.;Gain of sheet (P = 0.1208);
MVP		0.39
ClinPred		0.043	T
GERP RS		2.0
Varity_R		0.071
gMVP		0.29

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: rs202188959; hg19: chr11-88242335;