6-34022870-G-A

Position:

• chr6-34022870-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000841.4(GRM4):​c.2690C>T​(p.Ala897Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GRM4 NM_000841.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008787
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07314655).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRM4	NM_000841.4	c.2690C>T	p.Ala897Val	missense_variant, splice_region_variant	11/11	ENST00000538487.7	NP_000832.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRM4	ENST00000538487.7	c.2690C>T	p.Ala897Val	missense_variant, splice_region_variant	11/11	2	NM_000841.4	ENSP00000440556	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249280 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460992 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 726850

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.2690C>T (p.A897V) alteration is located in exon 10 (coding exon 10) of the GRM4 gene. This alteration results from a C to T substitution at nucleotide position 2690, causing the alanine (A) at amino acid position 897 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.21	.;.;T;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T;T;.;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.073	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	.;.;L;.;.;.;.
MutationTaster	Benign	0.85	D;D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.63	N;.;N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.10	T;.;T;D;.;T;T
Sift4G	Benign	0.38	T;T;T;T;T;T;T
Polyphen		0.025, 0.0020	.;B;B;.;.;.;.
Vest4		0.030
MutPred		0.34		.;.;Gain of catalytic residue at A897 (P = 0.0058);.;.;.;.;
MVP		0.60
MPC		0.57
ClinPred		0.12	T
GERP RS		0.77
Varity_R		0.042
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.056
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: rs1048408205; hg19: chr6-33990647;