Genetic Variant NM_000844.4:c.561T>C (chr3-7146493-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000844.4(GRM7):c.561T>C(p.Ser187Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00961 in 1,613,844 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0097 ( 111 hom. )

Consequence

GRM7
NM_000844.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.803

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 3-7146493-T-C is Benign according to our data. Variant chr3-7146493-T-C is described in ClinVar as Benign. ClinVar VariationId is 709766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.803 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0084 (1279/152230) while in subpopulation NFE AF = 0.0127 (863/68016). AF 95% confidence interval is 0.012. There are 14 homozygotes in GnomAd4. There are 647 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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.561T>C	p.Ser187Ser	synonymous	Exon 2 of 10	NP_000835.1
	GRM7	NM_181874.3		c.561T>C	p.Ser187Ser	synonymous	Exon 2 of 11	NP_870989.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GRM7	ENST00000357716.9	TSL:1 MANE Select	c.561T>C	p.Ser187Ser	synonymous	Exon 2 of 10	ENSP00000350348.4
GRM7	ENST00000389336.8	TSL:1	c.561T>C	p.Ser187Ser	synonymous	Exon 2 of 10	ENSP00000373987.4
GRM7	ENST00000389335.7	TSL:1	n.561T>C		non_coding_transcript_exon	Exon 2 of 11	ENSP00000373986.3

Frequencies

GnomAD3 genomes

AF:

0.00841

AC:

1280

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00793

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0127

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.00873

AC:

2194

AN:

251262

AF XY:

0.00858

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00538

Gnomad ASJ exome

AF:

0.0165

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0136

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00974

AC:

14234

AN:

1461614

Hom.:

111

Cov.:

AF XY:

0.00945

AC XY:

6868

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00129

AC:

AN:

33456

American (AMR)

AF:

0.00557

AC:

249

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0166

AC:

433

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00139

AC:

120

AN:

86242

European-Finnish (FIN)

AF:

0.0136

AC:

726

AN:

53420

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.0108

AC:

11971

AN:

1111922

Other (OTH)

AF:

0.0101

AC:

611

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

749

1498

2246

2995

3744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00840

AC:

1279

AN:

152230

Hom.:

Cov.:

AF XY:

0.00869

AC XY:

647

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41556

American (AMR)

AF:

0.00792

AC:

121

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0127

AC:

135

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0127

AC:

863

AN:

68016

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0115

Hom.:

Bravo

AF:

0.00784

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0107

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.2

(source)

DANN

Benign

0.39

PhyloP100

0.80

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over