3-6861502-C-A

Variant names:

• chr3-6861502-C-A
• rs114869468
• NM_000844.4:c.114C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000844.4(GRM7):​c.114C>A​(p.Tyr38*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y38Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GRM7 NM_000844.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.114C>A	p.Tyr38*	stop_gained	Exon 1 of 10	NP_000835.1	Q14831-1
	GRM7	NM_181874.3		c.114C>A	p.Tyr38*	stop_gained	Exon 1 of 11	NP_870989.1	Q14831-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	ENST00000357716.9	TSL:1 MANE Select	c.114C>A	p.Tyr38*	stop_gained	Exon 1 of 10	ENSP00000350348.4	Q14831-1
	GRM7	ENST00000389336.8	TSL:1	c.114C>A	p.Tyr38*	stop_gained	Exon 1 of 10	ENSP00000373987.4	Q14831-5
	GRM7	ENST00000389335.7	TSL:1	n.114C>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000373986.3	Q14831-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1425172 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 706502

African (AFR) AF: 0.00 AC: 0 AN: 32472

American (AMR) AF: 0.00 AC: 0 AN: 38540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23954

East Asian (EAS) AF: 0.00 AC: 0 AN: 38972

South Asian (SAS) AF: 0.00 AC: 0 AN: 80700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095956

Other (OTH) AF: 0.00 AC: 0 AN: 58852

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		1.5
Vest4		0.89
GERP RS		2.0
PromoterAI		0.049	Neutral
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114869468; hg19: chr3-6903189;