ENST00000640343.2:c.983-11513T>C

Variant names:

• chr4-56955143-T-C
• rs708547
• ENST00000640343.2:c.983-11513T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000640343.2	c.983-11513T>C		intron_variant	Intron 3 of 3	1		ENSP00000492813.1
REST	ENST00000640168.2	c.899-11513T>C		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.173 AC: 7156 AN: 41480

American (AMR) AF: 0.186 AC: 2844 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3466

East Asian (EAS) AF: 0.0161 AC: 83 AN: 5170

South Asian (SAS) AF: 0.171 AC: 827 AN: 4824

European-Finnish (FIN) AF: 0.227 AC: 2406 AN: 10586

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16953 AN: 67968

Other (OTH) AF: 0.235 AC: 497 AN: 2112

Alfa AF: 0.235 Hom.: 15176

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
PhyloP100		0.11

Splicing

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

Other links and lift over

dbSNP: rs708547; hg19: chr4-57821309;