rs10866440

Positions:

• chr4-56919620-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005612.5(REST):​c.899-167A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,124 control chromosomes in the GnomAD database, including 9,743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.35 (9743 hom., cov: 33)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.158

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-56919620-A-T is Benign according to our data. Variant chr4-56919620-A-T is described in ClinVar as [Benign]. Clinvar id is 1267836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REST	NM_005612.5	c.899-167A>T		intron_variant		ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.899-167A>T		intron_variant		1	NM_005612.5	ENSP00000311816	P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53360 AN: 152006 Hom.: 9735 Cov.: 33

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.370

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

GnomAD4 genome AF: 0.351 AC: 53369 AN: 152124 Hom.: 9743 Cov.: 33 AF XY: 0.352 AC XY: 26169 AN XY: 74354

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.235

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.364

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.364

Alfa AF: 0.367 Hom.: 1295

Bravo AF: 0.354

Asia WGS AF: 0.247 AC: 860 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.65

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: rs10866440; hg19: chr4-57785786;