4-56927585-G-T

Variant names:

• chr4-56927585-G-T
• rs1105434
• NM_005612.5:c.983-2256G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005612.5(REST):​c.983-2256G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 806,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.714
• Publications: 20 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REST	NM_005612.5	c.983-2256G>T		intron_variant	Intron 3 of 3	ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.983-2256G>T		intron_variant	Intron 3 of 3	1	NM_005612.5	ENSP00000311816.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000248 AC: 2 AN: 806070 Hom.: 0 Cov.: 11 AF XY: 0.00000517 AC XY: 2 AN XY: 387186

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000669 AC: 1 AN: 14944

American (AMR) AF: 0.00 AC: 0 AN: 3624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7846

East Asian (EAS) AF: 0.00 AC: 0 AN: 4826

South Asian (SAS) AF: 0.0000272 AC: 1 AN: 36792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3436

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 701106

Other (OTH) AF: 0.00 AC: 0 AN: 27504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1629

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	1.1
DANN	Benign	0.64
PhyloP100		-0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1105434; hg19: chr4-57793751;