Variant chr11-88508843-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001143831.3(GRM5):c.3388G>A(p.Ala1130Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,555,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

GRM5
NM_001143831.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.154

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015354633).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM5	NM_001143831.3 link	c.3388G>A	p.Ala1130Thr	missense_variant	10/10	ENST00000305447.5	NP_001137303.1	P41594-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GRM5	ENST00000305447.5 link	c.3388G>A	p.Ala1130Thr	missense_variant	10/10	1	NM_001143831.3	ENSP00000306138.4	P41594-1
GRM5	ENST00000305432.9 link	c.3292G>A	p.Ala1098Thr	missense_variant	8/8	1		ENSP00000305905.5	P41594-2
GRM5	ENST00000455756.6 link	c.3292G>A	p.Ala1098Thr	missense_variant	9/9	2		ENSP00000405690.2	P41594-2
GRM5-AS1	ENST00000526448.1 link	n.4268C>T		non_coding_transcript_exon_variant	1/6	5

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0219

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000254

AC:

AN:

157456

Hom.:

AF XY:

0.0000116

AC XY:

AN XY:

86362

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:

0.0000625

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000449

AC:

AN:

1403278

Hom.:

Cov.:

AF XY:

0.0000461

AC XY:

AN XY:

693912

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:

0.00

Gnomad4 NFE exome

AF:

0.0000572

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.000138

AC:

AN:

151904

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74192

show subpopulations

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.000219

ExAC

AF:

0.0000169

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

Oct 19, 2024

The c.3388G>A (p.A1130T) 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 3388, causing the alanine (A) at amino acid position 1130 to be replaced by a threonine (T). 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

0.082

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

.;.;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.58

T;.;T

M_CAP

Pathogenic

0.77

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.0

.;.;L

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.56

T;T;T

Sift4G

Benign

0.70

T;T;T

Polyphen

0.11

B;B;B

Vest4

0.077

MVP

0.48

ClinPred

0.089

GERP RS

2.4

Varity_R

0.058

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

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