rs6847086

Variant names:

• chr4-56925698-G-A
• rs6847086
• NM_005612.5:c.983-4143G>A

Variant summary

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

The NM_005612.5(REST):​c.983-4143G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,028 control chromosomes in the GnomAD database, including 11,387 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 0.38 (11387 hom., cov: 33)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.551
• Publications: 5 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REST	NM_005612.5	c.983-4143G>A		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.983-4143G>A		intron_variant	Intron 3 of 3	1	NM_005612.5	ENSP00000311816.7

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57871 AN: 151910 Hom.: 11385 Cov.: 33

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.380

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

GnomAD4 genome AF: 0.381 AC: 57905 AN: 152028 Hom.: 11387 Cov.: 33 AF XY: 0.376 AC XY: 27970 AN XY: 74292

African (AFR) AF: 0.446 AC: 18479 AN: 41462

American (AMR) AF: 0.436 AC: 6658 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1052 AN: 3468

East Asian (EAS) AF: 0.251 AC: 1296 AN: 5166

South Asian (SAS) AF: 0.220 AC: 1064 AN: 4828

European-Finnish (FIN) AF: 0.381 AC: 4022 AN: 10548

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24096 AN: 67974

Other (OTH) AF: 0.377 AC: 795 AN: 2106

Alfa AF: 0.364 Hom.: 27300

Bravo AF: 0.393

Asia WGS AF: 0.295 AC: 1028 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.49
DANN	Benign	0.35
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs6847086; hg19: chr4-57791864;