rs362936

Positions:

chr6-146399690-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.76

Variant links:

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]

GRM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GRM1. . Gene score misZ 2.5817 (greater than the threshold 3.09). Trascript score misZ 3.6372 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia 44, autosomal recessive spinocerebellar ataxia 13.

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. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.2651G>A	p.Gly884Glu	missense_variant	7/8	ENST00000282753.6	NP_001264993.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM1	ENST00000282753.6 linkuse as main transcript	c.2651G>A	p.Gly884Glu	missense_variant	7/8	1	NM_001278064.2	ENSP00000282753	P1	Q13255-1

Frequencies

GnomAD3 genomes

AF:

0.0134

AC:

2033

AN:

152094

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0164

AC XY:

2159

AN XY:

132026

show subpopulations

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.:

AF XY:

0.0167

AC XY:

12082

AN XY:

724164

show subpopulations

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.:

Cov.:

AF XY:

0.0137

AC XY:

1019

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0140

AC:

ALSPAC

AF:

0.0169

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0182

AC:

2210

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -

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

- -

Autosomal recessive spinocerebellar ataxia 13

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jul 17, 2023

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of spinocerebellar ataxia, autosomal recessive 13 (MIM#614831), with 77 homozygotes in gnomAD v2. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.072

.;T;.;T;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.70

.;T;T;.;T

MetaRNN

Benign

0.0067

T;T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.68

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over