rs2229902

Variant names:

• chr3-7452730-A-T
• rs2229902
• NM_000844.4:c.1298A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000844.4(GRM7):​c.1298A>T​(p.Tyr433Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,611,904 control chromosomes in the GnomAD database, including 135,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8644 hom., cov: 32)
  • Exomes 𝑓: 0.40 (126425 hom.)
• Consequence: GRM7 NM_000844.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.90
• Publications: 31 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00291273).
• BP6: Variant 3-7452730-A-T is Benign according to our data. Variant chr3-7452730-A-T is described in ClinVar as Benign. ClinVar VariationId is 1168981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	NM_000844.4	MANE Select	c.1298A>T	p.Tyr433Phe	missense	Exon 6 of 10	NP_000835.1
	GRM7	NM_181874.3		c.1298A>T	p.Tyr433Phe	missense	Exon 6 of 11	NP_870989.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	ENST00000357716.9	TSL:1 MANE Select	c.1298A>T	p.Tyr433Phe	missense	Exon 6 of 10	ENSP00000350348.4
	GRM7	ENST00000389336.8	TSL:1	c.1298A>T	p.Tyr433Phe	missense	Exon 6 of 10	ENSP00000373987.4
	GRM7	ENST00000389335.7	TSL:1	n.1298A>T		non_coding_transcript_exon	Exon 6 of 11	ENSP00000373986.3

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45051 AN: 151968 Hom.: 8644 Cov.: 32

Gnomad AFR AF: 0.0863

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.0787

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.306 AC: 76767 AN: 250772 AF XY: 0.310

Gnomad AFR exome AF: 0.0758

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0820

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.438

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.398 AC: 580383 AN: 1459818 Hom.: 126425 Cov.: 33 AF XY: 0.390 AC XY: 283503 AN XY: 726324

African (AFR) AF: 0.0703 AC: 2352 AN: 33442

American (AMR) AF: 0.201 AC: 8970 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 7114 AN: 26120

East Asian (EAS) AF: 0.0808 AC: 3205 AN: 39680

South Asian (SAS) AF: 0.126 AC: 10878 AN: 86226

European-Finnish (FIN) AF: 0.409 AC: 21839 AN: 53384

Middle Eastern (MID) AF: 0.301 AC: 1733 AN: 5756

European-Non Finnish (NFE) AF: 0.453 AC: 502856 AN: 1110292

Other (OTH) AF: 0.355 AC: 21436 AN: 60302

GnomAD4 genome AF: 0.296 AC: 45050 AN: 152086 Hom.: 8644 Cov.: 32 AF XY: 0.292 AC XY: 21667 AN XY: 74318

African (AFR) AF: 0.0860 AC: 3572 AN: 41536

American (AMR) AF: 0.274 AC: 4191 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 938 AN: 3468

East Asian (EAS) AF: 0.0783 AC: 403 AN: 5148

South Asian (SAS) AF: 0.115 AC: 554 AN: 4820

European-Finnish (FIN) AF: 0.428 AC: 4521 AN: 10572

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29716 AN: 67952

Other (OTH) AF: 0.319 AC: 673 AN: 2110

Alfa AF: 0.379 Hom.: 3882

Bravo AF: 0.283

TwinsUK AF: 0.474 AC: 1759

ALSPAC AF: 0.459 AC: 1768

ESP6500AA AF: 0.0978 AC: 431

ESP6500EA AF: 0.435 AC: 3743

ExAC AF: 0.304 AC: 36926

Asia WGS AF: 0.110 AC: 382 AN: 3478

EpiCase AF: 0.429

EpiControl AF: 0.440

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N
PhyloP100		1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.68	T
Sift4G	Benign	0.69	T
Polyphen		0.30	B
Vest4		0.11
MPC		0.54
ClinPred		0.013	T
GERP RS		3.4
Varity_R		0.25
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229902; hg19: chr3-7494417; COSMIC: COSV63142566;