dbSNP rs779854731: GRM5:p.Ala1130Ser (chr11-88508843-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001143831.3(GRM5):c.3388G>T(p.Ala1130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1130V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

GRM5
NM_001143831.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.154

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14384654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM5	NM_001143831.3 link	c.3388G>T	p.Ala1130Ser	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.3388G>T	p.Ala1130Ser	missense_variant	Exon 10 of 10	1	NM_001143831.3	ENSP00000306138.4	P41594-1
GRM5	ENST00000305432.9 link	c.3292G>T	p.Ala1098Ser	missense_variant	Exon 8 of 8	1		ENSP00000305905.5	P41594-2
GRM5	ENST00000455756.6 link	c.3292G>T	p.Ala1098Ser	missense_variant	Exon 9 of 9	2		ENSP00000405690.2	P41594-2
GRM5-AS1	ENST00000526448.1 link	n.4268C>A		non_coding_transcript_exon_variant	Exon 1 of 6	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1403278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693912

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30270

American (AMR)

AF:

0.00

AC:

AN:

36538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24794

East Asian (EAS)

AF:

0.00

AC:

AN:

35402

South Asian (SAS)

AF:

0.00

AC:

AN:

79348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083638

Other (OTH)

AF:

0.00

AC:

AN:

58162

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

7.7

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.081

.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.54

T;.;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.14

.;.;N

PhyloP100

0.15

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.060

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.75

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

0.018

B;B;B

Vest4

0.13

MutPred

0.20

.;.;Gain of glycosylation at A1130 (P = 0.0045);

MVP

0.42

ClinPred

0.13

GERP RS

2.4

Varity_R

0.069

gMVP

0.32

Mutation Taster

=78/22

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over