rs362936

chr6-146399690-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278064.2(GRM1):c.2651G>A(p.Gly884Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,607,602 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.017 (309 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.76

Genes affected

GRM1 (HGNC:4593): (glutamate metabotropic receptor 1) This gene encodes a metabotropic glutamate receptor that functions by activating phospholipase C. L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The canonical alpha isoform of the encoded protein is a disulfide-linked homodimer whose activity is mediated by a G-protein-coupled phosphatidylinositol-calcium second messenger system. This gene may be associated with many disease states, including schizophrenia, bipolar disorder, depression, and breast cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GRM1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066556633).
• BP6: Variant 6-146399690-G-A is Benign according to our data. Variant chr6-146399690-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 995113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0134 (2033/152212) while in subpopulation NFE AF= 0.0189 (1282/68008). AF 95% confidence interval is 0.018. There are 22 homozygotes in gnomad4. There are 1019 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.2651G>A	p.Gly884Glu	missense_variant	7/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.2651G>A	p.Gly884Glu	missense_variant	7/8	1	NM_001278064.2	P1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2033 AN: 152094 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.0164 AC: 3992 AN: 243170 Hom.: 68 AF XY: 0.0164 AC XY: 2159 AN XY: 132026

Gnomad AFR exome AF: 0.00287

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000694

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0172 AC: 24981 AN: 1455390 Hom.: 309 Cov.: 33 AF XY: 0.0167 AC XY: 12082 AN XY: 724164

Gnomad4 AFR exome AF: 0.00240

Gnomad4 AMR exome AF: 0.00545

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000651

Gnomad4 FIN exome AF: 0.0483

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0134 AC: 2033 AN: 152212 Hom.: 22 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74422

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.0439

Gnomad4 NFE AF: 0.0189

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.0159 Hom.: 34

Bravo AF: 0.0102

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0147 AC: 126

ExAC AF: 0.0182 AC: 2210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 26, 2019

- -

Autosomal recessive spinocerebellar ataxia 13;C4521563:Spinocerebellar ataxia 44 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0067	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.32	N;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T;T;T;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.98	D;D;.;D;D
Vest4		0.21
MPC		0.90
ClinPred		0.037	T
GERP RS		5.7
Varity_R		0.32
gMVP		0.40

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: rs362936; hg19: chr6-146720826;