rs6847086

Positions:

• chr4-56925698-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005612.5(REST):​c.983-4143G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,028 control chromosomes in the GnomAD database, including 11,387 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 0.38 (11387 hom., cov: 33)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551

Genes affected

REST (HGNC:9966): (RE1 silencing transcription factor) This gene was initially identified as a transcriptional repressor that represses neuronal genes in non-neuronal tissues. However, depending on the cellular context, this gene can act as either an oncogene or a tumor suppressor. The encoded protein is a member of the Kruppel-type zinc finger transcription factor family. It represses transcription by binding a DNA sequence element called the neuron-restrictive silencer element. The protein is also found in undifferentiated neuronal progenitor cells and it is thought that this repressor may act as a master negative regulator of neurogenesis. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REST	NM_005612.5	c.983-4143G>A		intron_variant		ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.983-4143G>A		intron_variant		1	NM_005612.5	ENSP00000311816.7

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57871 AN: 151910 Hom.: 11385 Cov.: 33

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.380

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

GnomAD4 genome AF: 0.381 AC: 57905 AN: 152028 Hom.: 11387 Cov.: 33 AF XY: 0.376 AC XY: 27970 AN XY: 74292

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.436

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.377

Alfa AF: 0.356 Hom.: 10050

Bravo AF: 0.393

Asia WGS AF: 0.295 AC: 1028 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.49
DANN	Benign	0.35

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: rs6847086; hg19: chr4-57791864;