11-88508813-C-T

Variant names:

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

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 links:

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

GRM5-AS1 links:

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
GRM5	NM_001143831.3 link	c.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	UniProt
GRM5	ENST00000305447.5 link	c.3418G>A	p.Ala1140Thr	missense_variant	Exon 10 of 10	1	NM_001143831.3	ENSP00000306138.4	P41594-1
GRM5	ENST00000305432.9 link	c.3322G>A	p.Ala1108Thr	missense_variant	Exon 8 of 8	1		ENSP00000305905.5	P41594-2
GRM5	ENST00000455756.6 link	c.3322G>A	p.Ala1108Thr	missense_variant	Exon 9 of 9	2		ENSP00000405690.2	P41594-2
GRM5-AS1	ENST00000526448.1 link	n.4238C>T		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151928

Hom.:

Cov.:

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:

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:

AN:

1373216

Hom.:

Cov.:

AF XY:

0.0000517

AC XY:

AN XY:

677320

show subpopulations

African (AFR)

AF:

0.000806

AC:

AN:

28544

American (AMR)

AF:

0.0000610

AC:

AN:

32782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23772

East Asian (EAS)

AF:

0.00

AC:

AN:

32310

South Asian (SAS)

AF:

0.0000261

AC:

AN:

76772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47818

Middle Eastern (MID)

AF:

0.000900

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.0000271

AC:

AN:

1068766

Other (OTH)

AF:

0.000158

AC:

AN:

56898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000191

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.000651

AC:

AN:

41504

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67940

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000196

ExAC

AF:

0.00000940

AC:

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

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.4

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.081

.;.;T

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.51

T;.;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

.;.;N

PhyloP100

0.40

PrimateAI

Pathogenic

0.80

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

GERP RS

2.9

Varity_R

0.048

gMVP

0.30

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-88508813-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over