Genetic Variant GRM8:c.1358-38275A>G (chr7-126647773-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000845.3(GRM8):c.1358-38275A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.83 in 152,098 control chromosomes in the GnomAD database, including 52,851 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 0.83 ( 52851 hom., cov: 31)

Consequence

GRM8
NM_000845.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.26

Publications

1 publications found

Variant links:

Genes affected

GRM8 (HGNC:4600): (glutamate metabotropic receptor 8) L-glutamate is the major excitatory neurotransmitter in the central nervous system and 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 3 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. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

GRM8 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=-0.96).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000845.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRM8	NM_000845.3	MANE Select	c.1358-38275A>G	intron	N/A	NP_000836.2	O00222-1
GRM8	NM_001371086.1		c.1358-38275A>G	intron	N/A	NP_001358015.1	A0A9L9PYG5
GRM8	NM_001127323.1		c.1358-38275A>G	intron	N/A	NP_001120795.1	O00222-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRM8	ENST00000339582.7	TSL:5 MANE Select	c.1358-38275A>G	intron	N/A	ENSP00000344173.2	O00222-1
GRM8	ENST00000358373.8	TSL:1	c.1358-38275A>G	intron	N/A	ENSP00000351142.3	O00222-2
GRM8	ENST00000341617.7	TSL:1	n.1429-38275A>G	intron	N/A	ENSP00000345747.3	O00222-3

Frequencies

GnomAD3 genomes

AF:

0.830

AC:

126159

AN:

151980

Hom.:

52808

Cov.:

show subpopulations

Gnomad AFR

AF:

0.924

Gnomad AMI

AF:

0.739

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.812

Gnomad EAS

AF:

0.942

Gnomad SAS

AF:

0.792

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.807

Gnomad NFE

AF:

0.785

Gnomad OTH

AF:

0.817

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

GnomAD4 genome

AF:

0.830

AC:

126256

AN:

152098

Hom.:

52851

Cov.:

AF XY:

0.831

AC XY:

61785

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.924

AC:

38359

AN:

41512

American (AMR)

AF:

0.751

AC:

11463

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.812

AC:

2816

AN:

3468

East Asian (EAS)

AF:

0.942

AC:

4862

AN:

5160

South Asian (SAS)

AF:

0.792

AC:

3814

AN:

4814

European-Finnish (FIN)

AF:

0.845

AC:

8927

AN:

10564

Middle Eastern (MID)

AF:

0.803

AC:

236

AN:

294

European-Non Finnish (NFE)

AF:

0.785

AC:

53379

AN:

67996

Other (OTH)

AF:

0.819

AC:

1729

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1087

2175

3262

4350

5437

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<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:

0.825

Hom.:

6741

Bravo

AF:

0.827

Asia WGS

AF:

0.877

AC:

3047

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.3

(source)

DANN

Benign

0.61

PhyloP100

-1.3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over