11-88508960-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001143831.3(GRM5):​c.3271G>T​(p.Ala1091Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,590,892 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 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GRM5
NM_001143831.3 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.296
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-AS1 (HGNC:40265): (GRM5 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10207209).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRM5NM_001143831.3 linkc.3271G>T p.Ala1091Ser missense_variant Exon 10 of 10 ENST00000305447.5 NP_001137303.1 P41594-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRM5ENST00000305447.5 linkc.3271G>T p.Ala1091Ser missense_variant Exon 10 of 10 1 NM_001143831.3 ENSP00000306138.4 P41594-1
GRM5ENST00000305432.9 linkc.3175G>T p.Ala1059Ser missense_variant Exon 8 of 8 1 ENSP00000305905.5 P41594-2
GRM5ENST00000455756.6 linkc.3175G>T p.Ala1059Ser missense_variant Exon 9 of 9 2 ENSP00000405690.2 P41594-2
GRM5-AS1ENST00000526448.1 linkn.4364+21C>A intron_variant Intron 1 of 5 5

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152162
Hom.:
0
Cov.:
32
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000125
AC:
18
AN:
1438730
Hom.:
0
Cov.:
34
AF XY:
0.0000126
AC XY:
9
AN XY:
713224
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:
0.0000164
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74326
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:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000580
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000830
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3271G>T (p.A1091S) alteration is located in exon 9 (coding exon 9) of the GRM5 gene. This alteration results from a G to T substitution at nucleotide position 3271, causing the alanine (A) at amino acid position 1091 to be replaced by a serine (S). 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
0.063
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
16
DANN
Benign
0.90
DEOGEN2
Benign
0.083
.;.;T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.80
T;.;T
M_CAP
Pathogenic
0.73
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-0.82
T
MutationAssessor
Benign
0.0
.;.;N
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.13
N;N;N
REVEL
Benign
0.10
Sift
Benign
1.0
T;T;T
Sift4G
Benign
0.84
T;T;T
Polyphen
0.090
B;B;B
Vest4
0.059
MVP
0.36
ClinPred
0.069
T
GERP RS
-0.62
Varity_R
0.039
gMVP
0.33

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.

Other links and lift over

dbSNP: rs372721603; hg19: chr11-88242128; API