4-56920284-G-T

Variant names:

• chr4-56920284-G-T
• rs1713985
• NM_005612.5:c.982+414G>T

Variant summary

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

The NM_005612.5(REST):​c.982+414G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.914 in 151,268 control chromosomes in the GnomAD database, including 63,440 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 0.91 (63440 hom., cov: 27)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• Publications: 38 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005612.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	NM_005612.5	MANE Select	c.982+414G>T		intron	N/A	NP_005603.3
	REST	NM_001193508.2		c.982+414G>T		intron	N/A	NP_001180437.1
	REST	NM_001363453.3		c.982+414G>T		intron	N/A	NP_001350382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	ENST00000309042.12	TSL:1 MANE Select	c.982+414G>T		intron	N/A	ENSP00000311816.7
	REST	ENST00000514063.2	TSL:1	c.982+414G>T		intron	N/A	ENSP00000501649.1
	REST	ENST00000619101.5	TSL:1	c.982+414G>T		intron	N/A	ENSP00000484836.2

Frequencies

GnomAD3 genomes AF: 0.914 AC: 138180 AN: 151150 Hom.: 63382 Cov.: 27

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.923

Gnomad EAS AF: 0.717

Gnomad SAS AF: 0.755

Gnomad FIN AF: 0.913

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.907

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

GnomAD4 genome AF: 0.914 AC: 138296 AN: 151268 Hom.: 63440 Cov.: 27 AF XY: 0.911 AC XY: 67265 AN XY: 73842

African (AFR) AF: 0.970 AC: 39969 AN: 41200

American (AMR) AF: 0.908 AC: 13639 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.923 AC: 3200 AN: 3466

East Asian (EAS) AF: 0.717 AC: 3691 AN: 5148

South Asian (SAS) AF: 0.754 AC: 3594 AN: 4764

European-Finnish (FIN) AF: 0.913 AC: 9556 AN: 10470

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61691 AN: 67918

Other (OTH) AF: 0.904 AC: 1882 AN: 2082

Alfa AF: 0.906 Hom.: 280432

Bravo AF: 0.917

Asia WGS AF: 0.738 AC: 2568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	5.4
DANN	Benign	0.48
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1713985; hg19: chr4-57786450;