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GeneBe

rs3796530

Positions:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_005612.5(REST):​c.2229G>A​(p.Glu743=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,383,968 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00053 ( 10 hom. )

Consequence

REST
NM_005612.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.525
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-56931087-G-A is Benign according to our data. Variant chr4-56931087-G-A is described in ClinVar as [Benign]. Clinvar id is 789137.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.525 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000996 (130/130570) while in subpopulation EAS AF= 0.0207 (94/4544). AF 95% confidence interval is 0.0173. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd4 at 130 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RESTNM_005612.5 linkuse as main transcriptc.2229G>A p.Glu743= synonymous_variant 4/4 ENST00000309042.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RESTENST00000309042.12 linkuse as main transcriptc.2229G>A p.Glu743= synonymous_variant 4/41 NM_005612.5 P1Q13127-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000996
AC:
130
AN:
130492
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000349
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000296
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0206
Gnomad SAS
AF:
0.00152
Gnomad FIN
AF:
0.000338
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000154
Gnomad OTH
AF:
0.000539
GnomAD3 exomes
AF:
0.000847
AC:
210
AN:
247856
Hom.:
2
AF XY:
0.000888
AC XY:
119
AN XY:
134038
show subpopulations
Gnomad AFR exome
AF:
0.000126
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0108
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000448
Gnomad OTH exome
AF:
0.000494
GnomAD4 exome
AF:
0.000530
AC:
664
AN:
1253398
Hom.:
10
Cov.:
32
AF XY:
0.000563
AC XY:
353
AN XY:
626608
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0163
Gnomad4 SAS exome
AF:
0.000519
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000573
Gnomad4 OTH exome
AF:
0.000402
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000996
AC:
130
AN:
130570
Hom.:
1
Cov.:
32
AF XY:
0.00111
AC XY:
71
AN XY:
63916
show subpopulations
Gnomad4 AFR
AF:
0.000348
Gnomad4 AMR
AF:
0.000295
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0207
Gnomad4 SAS
AF:
0.00152
Gnomad4 FIN
AF:
0.000338
Gnomad4 NFE
AF:
0.000154
Gnomad4 OTH
AF:
0.000539
Alfa
AF:
0.0589
Hom.:
32
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000594

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.36
DANN
Benign
0.34
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.

Other links and lift over

dbSNP: rs3796530; hg19: chr4-57797253; COSMIC: COSV58360295; COSMIC: COSV58360295; API