Variant 4-56931248-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005612.5(REST):c.2390C>T(p.Pro797Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,614,070 control chromosomes in the GnomAD database, including 34,729 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.22 ( 3900 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30829 hom. )

Consequence

REST
NM_005612.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0250

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012218356).

BP6

Variant 4-56931248-C-T is Benign according to our data. Variant chr4-56931248-C-T is described in ClinVar as [Benign]. Clinvar id is 1168079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REST	NM_005612.5 link	c.2390C>T	p.Pro797Leu	missense_variant	4/4	ENST00000309042.12	NP_005603.3	Q13127-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12 link	c.2390C>T	p.Pro797Leu	missense_variant	4/4	1	NM_005612.5	ENSP00000311816.7		Q13127-1

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33902

AN:

152088

Hom.:

3892

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.182

Gnomad EAS

AF:

0.396

Gnomad SAS

AF:

0.235

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.209

GnomAD3 exomes

AF:

0.224

AC:

56154

AN:

251004

Hom.:

6717

AF XY:

0.222

AC XY:

30103

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.256

Gnomad AMR exome

AF:

0.220

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.402

Gnomad SAS exome

AF:

0.232

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.193

Gnomad OTH exome

AF:

0.201

GnomAD4 exome

AF:

0.201

AC:

293726

AN:

1461866

Hom.:

30829

Cov.:

AF XY:

0.202

AC XY:

146762

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.252

Gnomad4 AMR exome

AF:

0.218

Gnomad4 ASJ exome

AF:

0.172

Gnomad4 EAS exome

AF:

0.396

Gnomad4 SAS exome

AF:

0.234

Gnomad4 FIN exome

AF:

0.234

Gnomad4 NFE exome

AF:

0.188

Gnomad4 OTH exome

AF:

0.210

GnomAD4 genome

AF:

0.223

AC:

33930

AN:

152204

Hom.:

3900

Cov.:

AF XY:

0.225

AC XY:

16748

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.257

Gnomad4 AMR

AF:

0.208

Gnomad4 ASJ

AF:

0.182

Gnomad4 EAS

AF:

0.396

Gnomad4 SAS

AF:

0.235

Gnomad4 FIN

AF:

0.235

Gnomad4 NFE

AF:

0.193

Gnomad4 OTH

AF:

0.209

Alfa

AF:

0.195

Hom.:

5393

Bravo

AF:

0.221

TwinsUK

AF:

0.169

AC:

628

ALSPAC

AF:

0.186

AC:

718

ESP6500AA

AF:

0.254

AC:

1121

ESP6500EA

AF:

0.190

AC:

1636

ExAC

AF:

0.225

AC:

27298

Asia WGS

AF:

0.268

AC:

932

AN:

3478

EpiCase

AF:

0.181

EpiControl

AF:

0.182

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.1

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.099

LIST_S2

Benign

0.41

.;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.52

N;.

REVEL

Benign

0.0090

Sift

Benign

0.19

T;.

Sift4G

Benign

0.10

T;T

Polyphen

0.0010

B;B

Vest4

0.086

MPC

0.018

ClinPred

0.0026

GERP RS

0.38

Varity_R

0.017

gMVP

0.017

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