6-34035669-T-A

Position:

chr6-34035669-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000841.4(GRM4):c.2441A>T(p.Lys814Met) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GRM4
NM_000841.4 missense, splice_region

Scores

Splicing: ADA: 0.8308

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

Variant links:

Genes affected

GRM4 (HGNC:4596): (glutamate metabotropic receptor 4) 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 metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GRM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM4	NM_000841.4 linkuse as main transcript	c.2441A>T	p.Lys814Met	missense_variant, splice_region_variant	9/11	ENST00000538487.7	NP_000832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM4	ENST00000538487.7 linkuse as main transcript	c.2441A>T	p.Lys814Met	missense_variant, splice_region_variant	9/11	2	NM_000841.4	ENSP00000440556	P1	Q14833-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

137876

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00192

AC:

1523

AN:

791760

Hom.:

Cov.:

AF XY:

0.00182

AC XY:

724

AN XY:

398234

show subpopulations

Gnomad4 AFR exome

AF:

0.00216

Gnomad4 AMR exome

AF:

0.000748

Gnomad4 ASJ exome

AF:

0.00366

Gnomad4 EAS exome

AF:

0.00331

Gnomad4 SAS exome

AF:

0.000216

Gnomad4 FIN exome

AF:

0.000922

Gnomad4 NFE exome

AF:

0.00211

Gnomad4 OTH exome

AF:

0.00314

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

138024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

67218

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2020

This sequence change replaces lysine with methionine at codon 814 of the GRM4 protein (p.Lys814Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GRM4-related disease. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;.;D;.;.;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D;.;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.8

.;.;M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.1

D;.;D;D;.;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0020

D;.;D;D;.;D;D

Sift4G

Uncertain

0.0060

D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;.;.;.;.

Vest4

0.69

MutPred

0.67

.;.;Loss of ubiquitination at K814 (P = 0.0199);.;.;.;.;

MVP

0.72

MPC

1.7

ClinPred

0.99

GERP RS

4.4

Varity_R

0.46

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.83

dbscSNV1_RF

Pathogenic

0.73

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over