rs1105434

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-56927585-G-A
• chr4-56927585-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005612.5(REST):​c.983-2256G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 950,708 control chromosomes in the GnomAD database, including 61,905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9606 hom., cov: 32)
  • Exomes 𝑓: 0.36 (52299 hom.)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-56927585-G-A is Benign according to our data. Variant chr4-56927585-G-A is described in ClinVar as Benign. ClinVar VariationId is 1265482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53049 AN: 151872 Hom.: 9599 Cov.: 32

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.432

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.359 AC: 286426 AN: 798718 Hom.: 52299 Cov.: 11 AF XY: 0.360 AC XY: 138127 AN XY: 383786

African (AFR) AF: 0.220 AC: 3260 AN: 14836

American (AMR) AF: 0.438 AC: 1578 AN: 3606

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 3250 AN: 7768

East Asian (EAS) AF: 0.228 AC: 1089 AN: 4784

South Asian (SAS) AF: 0.317 AC: 11599 AN: 36572

European-Finnish (FIN) AF: 0.357 AC: 2132 AN: 5964

Middle Eastern (MID) AF: 0.462 AC: 1575 AN: 3410

European-Non Finnish (NFE) AF: 0.363 AC: 252307 AN: 694516

Other (OTH) AF: 0.353 AC: 9636 AN: 27262

GnomAD4 genome AF: 0.349 AC: 53057 AN: 151990 Hom.: 9606 Cov.: 32 AF XY: 0.350 AC XY: 26036 AN XY: 74320

African (AFR) AF: 0.255 AC: 10567 AN: 41420

American (AMR) AF: 0.433 AC: 6607 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1523 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1218 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1490 AN: 4826

European-Finnish (FIN) AF: 0.364 AC: 3839 AN: 10558

Middle Eastern (MID) AF: 0.483 AC: 142 AN: 294

European-Non Finnish (NFE) AF: 0.392 AC: 26630 AN: 67972

Other (OTH) AF: 0.362 AC: 764 AN: 2110

Alfa AF: 0.355 Hom.: 1629

Bravo AF: 0.353

Asia WGS AF: 0.248 AC: 861 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

REST-related disorder Benign:1

Jun 02, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	2.7
DANN	Benign	0.59
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1105434; hg19: chr4-57793751; COSMIC: COSV58363203;