3-6861610-C-A

Variant names:

• chr3-6861610-C-A
• rs3749380
• NM_000844.4:c.222C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000844.4(GRM7):​c.222C>A​(p.Asn74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N74N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRM7 NM_000844.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.466
• 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: 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=0.112595946).

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.222C>A	p.Asn74Lys	missense	Exon 1 of 10	NP_000835.1	Q14831-1
	GRM7	NM_181874.3		c.222C>A	p.Asn74Lys	missense	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.222C>A	p.Asn74Lys	missense	Exon 1 of 10	ENSP00000350348.4	Q14831-1
	GRM7	ENST00000389336.8	TSL:1	c.222C>A	p.Asn74Lys	missense	Exon 1 of 10	ENSP00000373987.4	Q14831-5
	GRM7	ENST00000389335.7	TSL:1	n.222C>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000373986.3	Q14831-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N
PhyloP100		0.47
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.069
Sift	Benign	0.82	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.32		Gain of methylation at N74 (P = 0.0086)
MVP		0.26
MPC		0.62
ClinPred		0.74	D
GERP RS		3.6
PromoterAI		-0.013	Neutral
Varity_R		0.28
gMVP		0.77
Mutation Taster		=32/68	disease causing

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

Other links and lift over

dbSNP: rs3749380; hg19: chr3-6903297;