4-56957310-C-T

Variant names:

• chr4-56957310-C-T
• rs17081935
• ENST00000640343.2:c.983-9346C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000640343.2(REST):​c.983-9346C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 152,008 control chromosomes in the GnomAD database, including 2,785 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 0.18 (2785 hom., cov: 32)
• Consequence: REST ENST00000640343.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.28
• Publications: 51 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.983-9346C>T		intron_variant	Intron 3 of 3	1		ENSP00000492813.1
REST	ENST00000640168.2	c.899-9346C>T		intron_variant	Intron 2 of 2	1		ENSP00000490969.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27975 AN: 151890 Hom.: 2781 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.181

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

GnomAD4 genome AF: 0.184 AC: 27998 AN: 152008 Hom.: 2785 Cov.: 32 AF XY: 0.188 AC XY: 13952 AN XY: 74278

African (AFR) AF: 0.124 AC: 5134 AN: 41504

American (AMR) AF: 0.193 AC: 2947 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 630 AN: 3464

East Asian (EAS) AF: 0.383 AC: 1976 AN: 5160

South Asian (SAS) AF: 0.235 AC: 1129 AN: 4812

European-Finnish (FIN) AF: 0.235 AC: 2477 AN: 10530

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13104 AN: 67984

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.192 Hom.: 8285

Bravo AF: 0.177

Asia WGS AF: 0.263 AC: 913 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.65
PhyloP100		-4.3

Splicing

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

Other links and lift over

dbSNP: rs17081935; hg19: chr4-57823476;