rs146753539

chr6-146434425-C-Gchr6-146434425-C-T

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.3214C>G(p.Pro1072Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 1,613,760 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1072S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (11 hom.)
• Consequence: GRM1 NM_001278064.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.36

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=0.004937917).
• BP6: Variant 6-146434425-C-G is Benign according to our data. Variant chr6-146434425-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 445990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-146434425-C-G is described in Lovd as [Benign]. Variant chr6-146434425-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (921/152352) while in subpopulation AFR AF= 0.0169 (701/41590). AF 95% confidence interval is 0.0158. There are 10 homozygotes in gnomad4. There are 433 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM1	NM_001278064.2	c.3214C>G	p.Pro1072Ala	missense_variant	8/8	ENST00000282753.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM1	ENST00000282753.6	c.3214C>G	p.Pro1072Ala	missense_variant	8/8	1	NM_001278064.2	P1

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 918 AN: 152234 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00253 AC: 621 AN: 245696 Hom.: 4 AF XY: 0.00225 AC XY: 302 AN XY: 133962

Gnomad AFR exome AF: 0.0151

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00160 AC: 2339 AN: 1461408 Hom.: 11 Cov.: 61 AF XY: 0.00157 AC XY: 1138 AN XY: 726994

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000895

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152352 Hom.: 10 Cov.: 33 AF XY: 0.00581 AC XY: 433 AN XY: 74496

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00680

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0153 AC: 67

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2018	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	13
Dann	Benign	0.94
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.68	T;.
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.11
Sift	Benign	0.080	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0080	B;B
Vest4		0.16
MVP		0.26
MPC		0.70
ClinPred		0.0017	T
GERP RS		2.9
Varity_R		0.054
gMVP		0.34

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: rs146753539; hg19: chr6-146755561;