11-88508813-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001143831.3(GRM5):​c.3418G>A​(p.Ala1140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000649 in 1,525,250 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 1 hom. )

Consequence

GRM5
NM_001143831.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.398

Publications

0 publications found
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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.060658365).
BS2
High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRM5NM_001143831.3 linkc.3418G>A p.Ala1140Thr 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.3418G>A p.Ala1140Thr missense_variant Exon 10 of 10 1 NM_001143831.3 ENSP00000306138.4 P41594-1
GRM5ENST00000305432.9 linkc.3322G>A p.Ala1108Thr missense_variant Exon 8 of 8 1 ENSP00000305905.5 P41594-2
GRM5ENST00000455756.6 linkc.3322G>A p.Ala1108Thr missense_variant Exon 9 of 9 2 ENSP00000405690.2 P41594-2
GRM5-AS1ENST00000526448.1 linkn.4238C>T non_coding_transcript_exon_variant Exon 1 of 6 5

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
151928
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000628
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000480
GnomAD2 exomes
AF:
0.0000423
AC:
5
AN:
118298
AF XY:
0.0000153
show subpopulations
Gnomad AFR exome
AF:
0.000980
Gnomad AMR exome
AF:
0.0000985
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000510
AC:
70
AN:
1373216
Hom.:
1
Cov.:
30
AF XY:
0.0000517
AC XY:
35
AN XY:
677320
show subpopulations
African (AFR)
AF:
0.000806
AC:
23
AN:
28544
American (AMR)
AF:
0.0000610
AC:
2
AN:
32782
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23772
East Asian (EAS)
AF:
0.00
AC:
0
AN:
32310
South Asian (SAS)
AF:
0.0000261
AC:
2
AN:
76772
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
47818
Middle Eastern (MID)
AF:
0.000900
AC:
5
AN:
5554
European-Non Finnish (NFE)
AF:
0.0000271
AC:
29
AN:
1068766
Other (OTH)
AF:
0.000158
AC:
9
AN:
56898
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.535
Heterozygous variant carriers
0
4
8
12
16
20
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000191
AC:
29
AN:
152034
Hom.:
1
Cov.:
32
AF XY:
0.000215
AC XY:
16
AN XY:
74328
show subpopulations
African (AFR)
AF:
0.000651
AC:
27
AN:
41504
American (AMR)
AF:
0.0000654
AC:
1
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5134
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10578
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67940
Other (OTH)
AF:
0.000475
AC:
1
AN:
2104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.494
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.000196
ExAC
AF:
0.00000940
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 20, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3418G>A (p.A1140T) 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 3418, causing the alanine (A) at amino acid position 1140 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
0.079
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
6.4
DANN
Benign
0.92
DEOGEN2
Benign
0.081
.;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.73
FATHMM_MKL
Benign
0.36
N
LIST_S2
Benign
0.51
T;.;T
M_CAP
Pathogenic
0.90
D
MetaRNN
Benign
0.061
T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.0
.;.;N
PhyloP100
0.40
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
0.010
N;N;N
REVEL
Benign
0.18
Sift
Benign
0.61
T;T;T
Sift4G
Benign
0.61
T;T;T
Polyphen
0.0010
B;B;B
Vest4
0.11
MVP
0.36
ClinPred
0.016
T
GERP RS
2.9
Varity_R
0.048
gMVP
0.30
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs760255529; hg19: chr11-88241981; API