rs2229902

chr3-7452730-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:1
• Conservation: PhyloP100: 1.90

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1168981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM7	NM_000844.4	c.1298A>T	p.Tyr433Phe	missense_variant	6/10	ENST00000357716.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM7	ENST00000357716.9	c.1298A>T	p.Tyr433Phe	missense_variant	6/10	1	NM_000844.4	P1

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

GnomAD3 exomes AF: 0.306 AC: 76767 AN: 250772 Hom.: 14795 AF XY: 0.310 AC XY: 41955 AN XY: 135512

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 SAS exome AF: 0.128

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

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.0808

Gnomad4 SAS exome AF: 0.126

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.355

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

Gnomad4 AFR AF: 0.0860

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.0783

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.437

Gnomad4 OTH AF: 0.319

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.64	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.51	N;N;N;.;.
MutationTaster	Benign	0.19	P;P;P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.68	T;T;T;.;T
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.30	B;B;B;.;.
Vest4		0.11
MPC		0.54
ClinPred		0.013	T
GERP RS		3.4
Varity_R		0.25
gMVP		0.25

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

LitVar

Other links and lift over

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