NM_000841.4:c.872+622C>G

Variant names:

• chr6-34061271-G-C
• rs6901097
• NM_000841.4:c.872+622C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000841.4(GRM4):​c.872+622C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.621 in 152,006 control chromosomes in the GnomAD database, including 29,563 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 0.62 (29552 hom., cov: 31)
  • Exomes 𝑓: 0.66 (11 hom.)
• Consequence: GRM4 NM_000841.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• Publications: 2 publications found

Genes affected

GRM4 (HGNC:4596): (glutamate metabotropic receptor 4) 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000841.4. 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
	GRM4	NM_000841.4	MANE Select	c.872+622C>G		intron	N/A	NP_000832.1
	GRM4	NM_001256811.3		c.872+622C>G		intron	N/A	NP_001243740.1
	GRM4	NM_001256809.3		c.665+622C>G		intron	N/A	NP_001243738.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRM4	ENST00000538487.7	TSL:2 MANE Select	c.872+622C>G		intron	N/A	ENSP00000440556.1
	GRM4	ENST00000609278.1	TSL:1	n.*109+622C>G		intron	N/A	ENSP00000477016.1
	GRM4	ENST00000609973.1	TSL:2	n.1019C>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94318 AN: 151838 Hom.: 29547 Cov.: 31

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.660 AC: 33 AN: 50 Hom.: 11 Cov.: 0 AF XY: 0.611 AC XY: 22 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.700 AC: 28 AN: 40

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.621 AC: 94368 AN: 151956 Hom.: 29552 Cov.: 31 AF XY: 0.618 AC XY: 45886 AN XY: 74260

African (AFR) AF: 0.671 AC: 27793 AN: 41442

American (AMR) AF: 0.516 AC: 7879 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2273 AN: 3470

East Asian (EAS) AF: 0.500 AC: 2565 AN: 5132

South Asian (SAS) AF: 0.675 AC: 3259 AN: 4826

European-Finnish (FIN) AF: 0.581 AC: 6135 AN: 10564

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42353 AN: 67924

Other (OTH) AF: 0.628 AC: 1328 AN: 2114

Alfa AF: 0.490 Hom.: 1293

Bravo AF: 0.622

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.92
DANN	Benign	0.68
PhyloP100		-2.0
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: rs6901097; hg19: chr6-34029048;