11-88508867-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

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

3
7
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.48

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

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 rank MANE Protein UniProt
GRM5NM_001143831.3 linkc.3364G>A p.Glu1122Lys 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.3364G>A p.Glu1122Lys missense_variant Exon 10 of 10 1 NM_001143831.3 ENSP00000306138.4 P41594-1
GRM5ENST00000305432.9 linkc.3268G>A p.Glu1090Lys missense_variant Exon 8 of 8 1 ENSP00000305905.5 P41594-2
GRM5ENST00000455756.6 linkc.3268G>A p.Glu1090Lys missense_variant Exon 9 of 9 2 ENSP00000405690.2 P41594-2
GRM5-AS1ENST00000526448.1 linkn.4292C>T non_coding_transcript_exon_variant Exon 1 of 6 5

Frequencies

GnomAD3 genomes
AF:
0.0000987
AC:
15
AN:
151980
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:
0.000206
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000400
AC:
8
AN:
200184
AF XY:
0.0000365
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 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.:
0
Cov.:
34
AF XY:
0.000206
AC XY:
146
AN XY:
710286
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31472
American (AMR)
AF:
0.00
AC:
0
AN:
40658
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25294
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37452
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81824
European-Finnish (FIN)
AF:
0.0000194
AC:
1
AN:
51480
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5722
European-Non Finnish (NFE)
AF:
0.000278
AC:
305
AN:
1098606
Other (OTH)
AF:
0.000135
AC:
8
AN:
59280
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
20
41
61
82
102
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
100
<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:
0.0000987
AC:
15
AN:
151980
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74226
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41422
American (AMR)
AF:
0.00
AC:
0
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5144
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10580
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.000206
AC:
14
AN:
67954
Other (OTH)
AF:
0.00
AC:
0
AN:
2082
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.545
Heterozygous variant carriers
0
1
2
4
5
6
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:
0.0000767
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000249
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 31, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
.;.;T
Eigen
Benign
0.13
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.92
D;.;D
M_CAP
Pathogenic
0.67
D
MetaRNN
Benign
0.30
T;T;T
MetaSVM
Uncertain
-0.041
T
MutationAssessor
Uncertain
2.0
.;.;M
PhyloP100
6.5
PrimateAI
Pathogenic
0.88
D
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
T
GERP RS
4.9
Varity_R
0.18
gMVP
0.59
Mutation Taster
=73/27
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: rs764586864; hg19: chr11-88242035; COSMIC: COSV59615926; COSMIC: COSV59615926; API