Genetic Variant GRM7:c.1376-3623C>T (chr3-7457960-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000844.4(GRM7):c.1376-3623C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,000 control chromosomes in the GnomAD database, including 22,938 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.52 ( 22938 hom., cov: 32)

Consequence

GRM7
NM_000844.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.118

Publications

12 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

GRM7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM7	NM_000844.4 link	c.1376-3623C>T		intron_variant	Intron 6 of 9	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.1376-3623C>T		intron_variant	Intron 6 of 9	1	NM_000844.4	ENSP00000350348.4		Q14831-1
GRM7	ENST00000440923.7 link	n.1376-3623C>T		intron_variant	Intron 6 of 11	2		ENSP00000412329.3		H7C3K2

Frequencies

GnomAD3 genomes

AF:

0.524

AC:

79532

AN:

151882

Hom.:

22925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.304

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.566

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.574

Gnomad FIN

AF:

0.657

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.664

Gnomad OTH

AF:

0.546

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.524

AC:

79577

AN:

152000

Hom.:

22938

Cov.:

AF XY:

0.521

AC XY:

38699

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.304

AC:

12591

AN:

41458

American (AMR)

AF:

0.476

AC:

7262

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

1963

AN:

3470

East Asian (EAS)

AF:

0.195

AC:

1007

AN:

5168

South Asian (SAS)

AF:

0.575

AC:

2766

AN:

4812

European-Finnish (FIN)

AF:

0.657

AC:

6930

AN:

10550

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.664

AC:

45149

AN:

67970

Other (OTH)

AF:

0.552

AC:

1166

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1741

3481

5222

6962

8703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.551

Hom.:

3988

Bravo

AF:

0.496

Asia WGS

AF:

0.443

AC:

1541

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.58

PhyloP100

-0.12

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over