4-56910349-G-A

Position:

• chr4-56910349-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005612.5(REST):​c.-9-281G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0671 in 152,258 control chromosomes in the GnomAD database, including 466 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.067 (466 hom., cov: 33)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00100

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-56910349-G-A is Benign according to our data. Variant chr4-56910349-G-A is described in ClinVar as [Benign]. Clinvar id is 1286888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REST	NM_005612.5	c.-9-281G>A		intron_variant		ENST00000309042.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REST	ENST00000309042.12	c.-9-281G>A		intron_variant		1	NM_005612.5	P1

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10217 AN: 152140 Hom.: 465 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0496

Gnomad ASJ AF: 0.0884

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0965

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0966

Gnomad OTH AF: 0.0670

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

GnomAD4 genome AF: 0.0671 AC: 10214 AN: 152258 Hom.: 466 Cov.: 33 AF XY: 0.0668 AC XY: 4972 AN XY: 74452

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.0884

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.0965

Gnomad4 NFE AF: 0.0967

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0865 Hom.: 122

Bravo AF: 0.0598

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs35055952; hg19: chr4-57776515;