Variant 11-88508867-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_001143831.3(GRM5):c.3364G>A(p.Glu1122Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,583,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

GRM5
NM_001143831.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

Variant links:

Genes affected

GRM5 (HGNC:4597): (glutamate metabotropic receptor 5) This gene encodes a member of the G-protein coupled receptor 3 protein family. The encoded protein is a metabatropic glutamate receptor, whose signaling activates a phosphatidylinositol-calcium second messenger system. This protein may be involved in the regulation of neural network activity and synaptic plasticity. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. A pseudogene of this gene has been defined on chromosome 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

GRM5 links:

GRM5-AS1 (HGNC:40265): (GRM5 antisense RNA 1)

GRM5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant where missense usually causes diseases, GRM5

BP4

Computational evidence support a benign effect (MetaRNN=0.30085415).

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM5	NM_001143831.3 linkuse as main transcript	c.3364G>A	p.Glu1122Lys	missense_variant	10/10	ENST00000305447.5
GRM5-AS1	NR_049724.1 linkuse as main transcript	n.4292C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM5	ENST00000305447.5 linkuse as main transcript	c.3364G>A	p.Glu1122Lys	missense_variant	10/10	1	NM_001143831.3	A2	P41594-1
GRM5	ENST00000305432.9 linkuse as main transcript	c.3268G>A	p.Glu1090Lys	missense_variant	8/8	1		P2	P41594-2
GRM5-AS1	ENST00000526448.1 linkuse as main transcript	n.4292C>T		non_coding_transcript_exon_variant	1/6	5
GRM5	ENST00000455756.6 linkuse as main transcript	c.3268G>A	p.Glu1090Lys	missense_variant	9/9	2		P2	P41594-2

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

200184

Hom.:

AF XY:

0.0000365

AC XY:

AN XY:

109502

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000794

Gnomad OTH exome

AF:

0.000203

GnomAD4 exome

AF:

0.000219

AC:

314

AN:

1431788

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

146

AN XY:

710286

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.000278

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151980

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000765

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.3364G>A (p.E1122K) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a G to A substitution at nucleotide position 3364, causing the glutamic acid (E) at amino acid position 1122 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Benign

0.13

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;.;D

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Uncertain

-0.041

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.5

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.085

T;T;T

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.93

P;P;P

Vest4

0.26

MVP

0.63

ClinPred

0.25

GERP RS

4.9

Varity_R

0.18

gMVP

0.59

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