6-34100631-G-T

Variant names:

• chr6-34100631-G-T
• rs733457
• NM_000841.4:c.520-8532C>A

Variant summary

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

The NM_000841.4(GRM4):​c.520-8532C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.597 in 152,146 control chromosomes in the GnomAD database, including 27,535 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 0.60 (27535 hom., cov: 33)
• Consequence: GRM4 NM_000841.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.898
• Publications: 8 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.658 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.520-8532C>A		intron	N/A	NP_000832.1
	GRM4	NM_001256811.3		c.520-8532C>A		intron	N/A	NP_001243740.1
	GRM4	NM_001256809.3		c.313-8532C>A		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.520-8532C>A		intron	N/A	ENSP00000440556.1
	GRM4	ENST00000607916.1	TSL:1	n.489-8532C>A		intron	N/A
	GRM4	ENST00000609278.1	TSL:1	n.519+32347C>A		intron	N/A	ENSP00000477016.1

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90849 AN: 152028 Hom.: 27525 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.486

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.594

Gnomad OTH AF: 0.635

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

GnomAD4 genome AF: 0.597 AC: 90887 AN: 152146 Hom.: 27535 Cov.: 33 AF XY: 0.591 AC XY: 43915 AN XY: 74364

African (AFR) AF: 0.665 AC: 27596 AN: 41498

American (AMR) AF: 0.542 AC: 8285 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2087 AN: 3470

East Asian (EAS) AF: 0.485 AC: 2506 AN: 5162

South Asian (SAS) AF: 0.609 AC: 2945 AN: 4832

European-Finnish (FIN) AF: 0.479 AC: 5070 AN: 10586

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.594 AC: 40408 AN: 67984

Other (OTH) AF: 0.627 AC: 1327 AN: 2116

Alfa AF: 0.476 Hom.: 1358

Bravo AF: 0.608

Asia WGS AF: 0.499 AC: 1736 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.16
DANN	Benign	0.60
PhyloP100		-0.90
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: rs733457; hg19: chr6-34068408;