rs4109037

Positions:

• chr4-56909443-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005612.5(REST):​c.-9-1187T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,338 control chromosomes in the GnomAD database, including 1,096 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.582

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REST	NM_005612.5	c.-9-1187T>A		intron_variant		ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.-9-1187T>A		intron_variant		1	NM_005612.5	ENSP00000311816	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15924 AN: 152150 Hom.: 1098 Cov.: 33

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.0940

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.129 AC: 9 AN: 70 Hom.: 0 Cov.: 0 AF XY: 0.130 AC XY: 7 AN XY: 54

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.0952

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.105 AC: 15917 AN: 152268 Hom.: 1096 Cov.: 33 AF XY: 0.103 AC XY: 7681 AN XY: 74448

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0940

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.129

Alfa AF: 0.128 Hom.: 184

Bravo AF: 0.103

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.79

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: rs4109037; hg19: chr4-57775609; COSMIC: COSV58361959; COSMIC: COSV58361959;