4-56955143-T-C

Position:

• chr4-56955143-T-C

Variant summary

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

The ENST00000640343.2(REST):​c.983-11513T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,086 control chromosomes in the GnomAD database, including 3,577 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 0.21 (3577 hom., cov: 31)
• Consequence: REST ENST00000640343.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.56955143T>C		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000640343.2	c.983-11513T>C		intron_variant		1		ENSP00000492813.1
REST	ENST00000640168.2	c.899-11513T>C		intron_variant		1		ENSP00000490969.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31925 AN: 151966 Hom.: 3580 Cov.: 31

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.238

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.210 AC: 31918 AN: 152086 Hom.: 3577 Cov.: 31 AF XY: 0.205 AC XY: 15259 AN XY: 74356

Gnomad4 AFR AF: 0.173

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.235

Alfa AF: 0.238 Hom.: 7641

Bravo AF: 0.205

Asia WGS AF: 0.120 AC: 418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.2
DANN	Benign	0.57

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs708547; hg19: chr4-57821309;