rs1105434

chr4-56927585-G-Achr4-56927585-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005612.5(REST):c.983-2256G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 950,708 control chromosomes in the GnomAD database, including 61,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9606 hom., cov: 32)
  • Exomes 𝑓: 0.36 (52299 hom.)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.714

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-56927585-G-A is Benign according to our data. Variant chr4-56927585-G-A is described in ClinVar as [Benign]. Clinvar id is 1265482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REST	NM_005612.5	c.983-2256G>A		intron_variant		ENST00000309042.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REST	ENST00000309042.12	c.983-2256G>A		intron_variant		1	NM_005612.5	P1

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53049 AN: 151872 Hom.: 9599 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.359 AC: 286426 AN: 798718 Hom.: 52299 Cov.: 11 AF XY: 0.360 AC XY: 138127 AN XY: 383786

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.317

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.353

GnomAD4 genome AF: 0.349 AC: 53057 AN: 151990 Hom.: 9606 Cov.: 32 AF XY: 0.350 AC XY: 26036 AN XY: 74320

Gnomad4 AFR AF: 0.255

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.362

Alfa AF: 0.358 Hom.: 1598

Bravo AF: 0.353

Asia WGS AF: 0.248 AC: 861 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2019

- -

REST-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	2.7
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1105434; hg19: chr4-57793751; COSMIC: COSV58363203;