5-178981529-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000843.4(GRM6):c.*128G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0324 in 705,758 control chromosomes in the GnomAD database, including 543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (80 hom., cov: 32)
  • Exomes 𝑓: 0.034 (463 hom.)
• Consequence: GRM6 NM_000843.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.839

Genes affected

GRM6 (HGNC:4598): (glutamate metabotropic receptor 6) 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. Mutations in this gene result in congenital stationary night blindness type 1B. [provided by RefSeq, May 2018]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-178981529-C-T is Benign according to our data. Variant chr5-178981529-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1707172.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRM6	NM_000843.4	c.*128G>A		3_prime_UTR_variant	11/11	ENST00000517717.3
ZNF454	XR_007058600.1	n.5644-8218C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRM6	ENST00000517717.3	c.*128G>A		3_prime_UTR_variant	11/11	5	NM_000843.4	P1
	ENST00000519491.1	n.305-8218C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3885 AN: 152022 Hom.: 79 Cov.: 32

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0354

GnomAD4 exome AF: 0.0343 AC: 18988 AN: 553618 Hom.: 463 Cov.: 7 AF XY: 0.0376 AC XY: 10888 AN XY: 289618

Gnomad4 AFR exome AF: 0.00693

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.0555

Gnomad4 EAS exome AF: 0.000188

Gnomad4 SAS exome AF: 0.0808

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0255 AC: 3883 AN: 152140 Hom.: 80 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74380

Gnomad4 AFR AF: 0.00542

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.0734

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0351

Alfa AF: 0.0326 Hom.: 11

Bravo AF: 0.0221

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 28, 2020

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.0
Dann	Benign	0.57

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: rs114396608; hg19: chr5-178408530;