Genetic Variant GRM7:p.Pro66Ser (chr3-6861584-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000844.4(GRM7):c.196C>T(p.Pro66Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000893 in 1,455,860 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: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GRM7
NM_000844.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

Variant links:

Genes affected

GRM7 (HGNC:4599): (glutamate metabotropic receptor 7) L-glutamate is the major excitatory neurotransmitter in the central nervous system, and it activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors that have been divided into three groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5, and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3, while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

GRM7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3484646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM7	NM_000844.4 link	c.196C>T	p.Pro66Ser	missense_variant	Exon 1 of 10	ENST00000357716.9	NP_000835.1	Q14831-1B2R693Q59G95

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM7	ENST00000357716.9 link	c.196C>T	p.Pro66Ser	missense_variant	Exon 1 of 10	1	NM_000844.4	ENSP00000350348.4		Q14831-1
GRM7	ENST00000440923.7 link	n.196C>T		non_coding_transcript_exon_variant	Exon 1 of 12	2		ENSP00000412329.3		H7C3K2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000415

AC:

AN:

240936

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130732

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000930

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000893

AC:

AN:

1455860

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723586

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.196C>T (p.P66S) alteration is located in exon 1 (coding exon 1) of the GRM7 gene. This alteration results from a C to T substitution at nucleotide position 196, causing the proline (P) at amino acid position 66 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

0.16

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.099

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.76

P;B;P

Vest4

0.52

MutPred

0.31

Loss of glycosylation at S63 (P = 0.0712);Loss of glycosylation at S63 (P = 0.0712);Loss of glycosylation at S63 (P = 0.0712);

MVP

0.39

MPC

1.3

ClinPred

0.85

GERP RS

5.4

Varity_R

0.24

gMVP

0.76

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over