rs2228991

Positions:

• chr4-56930734-G-A
• chr4-56930734-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 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 0.087 (877 hom., cov: 33)
  • Exomes 𝑓: 0.051 (3834 hom.)
• Consequence: REST NM_005612.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
REST	NM_005612.5	c.1876G>A	p.Val626Ile	missense_variant	4/4	ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.1876G>A	p.Val626Ile	missense_variant	4/4	1	NM_005612.5	ENSP00000311816.7

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13167 AN: 152068 Hom.: 870 Cov.: 33

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

GnomAD3 exomes AF: 0.0887 AC: 20960 AN: 236230 Hom.: 1945 AF XY: 0.0768 AC XY: 9852 AN XY: 128344

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 SAS exome AF: 0.0128

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.: 33 AF XY: 0.0488 AC XY: 35150 AN XY: 720890

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.0120

Gnomad4 FIN exome AF: 0.0695

Gnomad4 NFE exome AF: 0.0385

Gnomad4 OTH exome AF: 0.0574

GnomAD4 genome AF: 0.0866 AC: 13177 AN: 152186 Hom.: 877 Cov.: 33 AF XY: 0.0889 AC XY: 6617 AN XY: 74406

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.0711

Gnomad4 NFE AF: 0.0425

Gnomad4 OTH AF: 0.0776

Alfa AF: 0.0533 Hom.: 166

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

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	Feb 28, 2019	This variant is associated with the following publications: (PMID: 22530801) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.29	.;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.21	T
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	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.0091

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

Other links and lift over

dbSNP: rs2228991; hg19: chr4-57796900;