6-146434425-C-T

Position:

chr6-146434425-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001278064.2(GRM1):c.3214C>T(p.Pro1072Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000424 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1072A) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

GRM1
NM_001278064.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.36

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 Likely_benign. Variant got -1 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=0.075071454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM1	NM_001278064.2 linkuse as main transcript	c.3214C>T	p.Pro1072Ser	missense_variant	8/8	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.3214C>T	p.Pro1072Ser	missense_variant	8/8	1	NM_001278064.2	ENSP00000282753	P1	Q13255-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000488

AC:

AN:

245696

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

133962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000554

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000819

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000495

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2022

The c.3214C>T (p.P1072S) alteration is located in exon 9 (coding exon 8) of the GRM1 gene. This alteration results from a C to T substitution at nucleotide position 3214, causing the proline (P) at amino acid position 1072 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GRM1-related conditions. This variant is present in population databases (rs146753539, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1072 of the GRM1 protein (p.Pro1072Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.63

T;.

M_CAP

Benign

0.054

MetaRNN

Benign

0.075

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.084

Sift

Benign

0.19

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.019

B;B

Vest4

0.15

MVP

0.28

MPC

0.74

ClinPred

0.039

GERP RS

2.9

Varity_R

0.057

gMVP

0.41

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