3-7654348-T-A

Variant names:

• chr3-7654348-T-A
• rs7627369
• NM_000844.4:c.2452-25701T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000844.4(GRM7):​c.2452-25701T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 152,210 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.022 (62 hom., cov: 32)
• Consequence: GRM7 NM_000844.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.353
• Publications: 1 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

ENSG00000270207 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0225 (3423/152210) while in subpopulation AFR AF = 0.0333 (1384/41542). AF 95% confidence interval is 0.0319. There are 62 homozygotes in GnomAd4. There are 1626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	NM_000844.4	MANE Select	c.2452-25701T>A		intron	N/A	NP_000835.1
	GRM7	NM_181874.3		c.2452-25701T>A		intron	N/A	NP_870989.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM7	ENST00000357716.9	TSL:1 MANE Select	c.2452-25701T>A		intron	N/A	ENSP00000350348.4
	GRM7	ENST00000389336.8	TSL:1	c.2452-25701T>A		intron	N/A	ENSP00000373987.4
	GRM7	ENST00000389335.7	TSL:1	n.2452-25701T>A		intron	N/A	ENSP00000373986.3

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3415 AN: 152092 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0201

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0139

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.00915

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0388

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0225 AC: 3423 AN: 152210 Hom.: 62 Cov.: 32 AF XY: 0.0218 AC XY: 1626 AN XY: 74424

African (AFR) AF: 0.0333 AC: 1384 AN: 41542

American (AMR) AF: 0.0201 AC: 308 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3472

East Asian (EAS) AF: 0.0140 AC: 72 AN: 5154

South Asian (SAS) AF: 0.00831 AC: 40 AN: 4816

European-Finnish (FIN) AF: 0.00915 AC: 97 AN: 10606

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0148 AC: 1008 AN: 68012

Other (OTH) AF: 0.0384 AC: 81 AN: 2112

Alfa AF: 0.0212 Hom.: 4

Bravo AF: 0.0240

Asia WGS AF: 0.0260 AC: 90 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.67
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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: rs7627369; hg19: chr3-7696035;