rs3796529

Variant names:

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.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. 15/21 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 Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P797P) has been classified as Likely benign.

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

Publications

68 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=0.0012218356).

BP6

Variant 4-56931248-C-T is Benign according to our data. Variant chr4-56931248-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
REST	NM_005612.5 link	c.2390C>T	p.Pro797Leu	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.2390C>T	p.Pro797Leu	missense_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.224

AC:

56154

AN:

251004

AF XY:

0.222

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 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

African (AFR)

AF:

0.252

AC:

8426

AN:

33480

American (AMR)

AF:

0.218

AC:

9763

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

4504

AN:

26136

East Asian (EAS)

AF:

0.396

AC:

15727

AN:

39700

South Asian (SAS)

AF:

0.234

AC:

20181

AN:

86256

European-Finnish (FIN)

AF:

0.234

AC:

12481

AN:

53408

Middle Eastern (MID)

AF:

0.165

AC:

951

AN:

5768

European-Non Finnish (NFE)

AF:

0.188

AC:

208986

AN:

1112000

Other (OTH)

AF:

0.210

AC:

12707

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16323

32645

48968

65290

81613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7452

14904

22356

29808

37260

<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:

0.223

AC:

33930

AN:

152204

Hom.:

3900

Cov.:

AF XY:

0.225

AC XY:

16748

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.257

AC:

10682

AN:

41524

American (AMR)

AF:

0.208

AC:

3176

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.182

AC:

631

AN:

3470

East Asian (EAS)

AF:

0.396

AC:

2048

AN:

5170

South Asian (SAS)

AF:

0.235

AC:

1133

AN:

4826

European-Finnish (FIN)

AF:

0.235

AC:

2487

AN:

10598

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.193

AC:

13115

AN:

68026

Other (OTH)

AF:

0.209

AC:

441

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1413

2826

4239

5652

7065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.200

Hom.:

8636

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

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

- -

Oct 15, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

-0.025

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

Mutation Taster

=97/3

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