dbSNP rs1105434: REST:c.983-2256G>A (chr4-56927585-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.714

Variant links:

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]

REST links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
REST	NM_005612.5 link	c.983-2256G>A		intron_variant	Intron 3 of 3	ENST00000309042.12	NP_005603.3	Q13127-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12 link	c.983-2256G>A		intron_variant	Intron 3 of 3	1	NM_005612.5	ENSP00000311816.7		Q13127-1

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53049

AN:

151872

Hom.:

9599

Cov.:

show subpopulations

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.:

AF XY:

0.360

AC XY:

138127

AN XY:

383786

show subpopulations

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.:

AF XY:

0.350

AC XY:

26036

AN XY:

74320

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

REST-related disorder

Benign:1

Jun 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over