NM_000840.3:c.1325-16183G>A

Variant names:

• chr7-86822656-G-A
• rs2299227
• NM_000840.3:c.1325-16183G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000840.3(GRM3):​c.1325-16183G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 152,218 control chromosomes in the GnomAD database, including 103 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 0.028 (103 hom., cov: 32)
• Consequence: GRM3 NM_000840.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714

Genes affected

GRM3 (HGNC:4595): (glutamate metabotropic receptor 3) L-glutamate is the major excitatory neurotransmitter in the central nervous system and 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 3 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.028 (4269/152218) while in subpopulation NFE AF= 0.0469 (3186/67996). AF 95% confidence interval is 0.0455. There are 103 homozygotes in gnomad4. There are 1945 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRM3	NM_000840.3	c.1325-16183G>A		intron_variant	Intron 3 of 5	ENST00000361669.7	NP_000831.2
GRM3	NM_001363522.2	c.1325-27714G>A		intron_variant	Intron 3 of 4		NP_001350451.1
GRM3	XM_047420268.1	c.1325-16183G>A		intron_variant	Intron 4 of 6		XP_047276224.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRM3	ENST00000361669.7	c.1325-16183G>A		intron_variant	Intron 3 of 5	1	NM_000840.3	ENSP00000355316.2
GRM3	ENST00000439827.1	c.1325-27714G>A		intron_variant	Intron 3 of 4	1		ENSP00000398767.1

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4270 AN: 152100 Hom.: 103 Cov.: 32

Gnomad AFR AF: 0.00823

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0178

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

GnomAD4 genome AF: 0.0280 AC: 4269 AN: 152218 Hom.: 103 Cov.: 32 AF XY: 0.0261 AC XY: 1945 AN XY: 74442

Gnomad4 AFR AF: 0.00821

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0469

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0331 Hom.: 16

Bravo AF: 0.0268

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.70

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: rs2299227; hg19: chr7-86451972;