3-6861430-G-A

Variant names:

Variant summary

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

The NM_000844.4(GRM7):c.42G>A(p.Met14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,599,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GRM7
NM_000844.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.53

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

GRM7 links:

Genome browser will be placed here

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=0.13173953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	NM_000844.4	MANE Select	c.42G>A	p.Met14Ile	missense	Exon 1 of 10	NP_000835.1	Q14831-1
	GRM7	NM_181874.3		c.42G>A	p.Met14Ile	missense	Exon 1 of 11	NP_870989.1	Q14831-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GRM7	ENST00000357716.9	TSL:1 MANE Select	c.42G>A	p.Met14Ile	missense	Exon 1 of 10	ENSP00000350348.4	Q14831-1
GRM7	ENST00000389336.8	TSL:1	c.42G>A	p.Met14Ile	missense	Exon 1 of 10	ENSP00000373987.4	Q14831-5
GRM7	ENST00000389335.7	TSL:1	n.42G>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000373986.3	Q14831-4

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.00

GnomAD2 exomes

AF:

0.00000439

AC:

AN:

227656

AF XY:

0.00000799

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000312

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:

0.00000138

AC:

AN:

1448508

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720322

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:

32996

American (AMR)

AF:

0.0000472

AC:

AN:

42380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25260

East Asian (EAS)

AF:

0.00

AC:

AN:

39490

South Asian (SAS)

AF:

0.00

AC:

AN:

84562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107006

Other (OTH)

AF:

0.00

AC:

AN:

59818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.300

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41240

American (AMR)

AF:

0.0000658

AC:

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

4926

South Asian (SAS)

AF:

0.00

AC:

AN:

4620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67814

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.0020

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.69

PhyloP100

2.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.46

REVEL

Benign

0.24

Sift

Benign

0.40

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.22

MutPred

0.68

Gain of sheet (P = 0.0073)

MVP

0.40

MPC

0.59

ClinPred

0.32

GERP RS

5.1

PromoterAI

0.015

Neutral

(source)

Varity_R

0.15

gMVP

0.54

Mutation Taster

=95/5

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over