rs2228991

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005612.5(REST):c.1876G>A(p.Val626Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,601,638 control chromosomes in the GnomAD database, including 4,711 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V626L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.087 ( 877 hom., cov: 33)

Exomes 𝑓: 0.051 ( 3834 hom. )

Consequence

REST
NM_005612.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.09

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

fibromatosis, gingival, 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Wilms tumor 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
hereditary gingival fibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nonsyndromic hearing loss 27
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

REST links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005392164).

BP6

Variant 4-56930734-G-A is Benign according to our data. Variant chr4-56930734-G-A is described in ClinVar as [Benign]. Clinvar id is 1166565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REST	NM_005612.5 link	c.1876G>A	p.Val626Ile	missense_variant	Exon 4 of 4	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.1876G>A	p.Val626Ile	missense_variant	Exon 4 of 4	1	NM_005612.5	ENSP00000311816.7		Q13127-1

Frequencies

GnomAD3 genomes

AF:

0.0866

AC:

13167

AN:

152068

Hom.:

870

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.0711

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0425

Gnomad OTH

AF:

0.0793

GnomAD2 exomes

AF:

0.0887

AC:

20960

AN:

236230

AF XY:

0.0768

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.272

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.223

Gnomad FIN exome

AF:

0.0739

Gnomad NFE exome

AF:

0.0392

Gnomad OTH exome

AF:

0.0701

GnomAD4 exome

AF:

0.0512

AC:

74225

AN:

1449452

Hom.:

3834

Cov.:

AF XY:

0.0488

AC XY:

35150

AN XY:

720890

show subpopulations

African (AFR)

AF:

0.128

AC:

4162

AN:

32558

American (AMR)

AF:

0.262

AC:

10699

AN:

40812

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

412

AN:

25274

East Asian (EAS)

AF:

0.203

AC:

8057

AN:

39648

South Asian (SAS)

AF:

0.0120

AC:

1006

AN:

84140

European-Finnish (FIN)

AF:

0.0695

AC:

3687

AN:

53056

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.0385

AC:

42683

AN:

1108592

Other (OTH)

AF:

0.0574

AC:

3427

AN:

59722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

4286

8573

12859

17146

21432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1774

3548

5322

7096

8870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0866

AC:

13177

AN:

152186

Hom.:

877

Cov.:

AF XY:

0.0889

AC XY:

6617

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.124

AC:

5144

AN:

41526

American (AMR)

AF:

0.194

AC:

2971

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

AN:

3470

East Asian (EAS)

AF:

0.215

AC:

1108

AN:

5148

South Asian (SAS)

AF:

0.0158

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0711

AC:

754

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0425

AC:

2888

AN:

68014

Other (OTH)

AF:

0.0776

AC:

164

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

593

1186

1780

2373

2966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0428

Hom.:

174

Bravo

AF:

0.102

TwinsUK

AF:

0.0375

AC:

139

ALSPAC

AF:

0.0405

AC:

156

ESP6500AA

AF:

0.120

AC:

527

ESP6500EA

AF:

0.0405

AC:

348

ExAC

AF:

0.0812

AC:

9850

Asia WGS

AF:

0.108

AC:

374

AN:

3478

EpiCase

AF:

0.0325

EpiControl

AF:

0.0333

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 28, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22530801) -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.55

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.29

.;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

N;N

PhyloP100

-1.1

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.16

N;.

REVEL

Benign

0.016

Sift

Benign

0.24

T;.

Sift4G

Benign

0.27

T;T

Polyphen

0.017

B;B

Vest4

0.0080

MPC

0.017

ClinPred

0.0040

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.0091

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over