rs10866440

Variant names:

• chr4-56919620-A-T
• rs10866440
• NM_005612.5:c.899-167A>T

Variant summary

Our verdict is Benign. The variant received -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
• 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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 -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	NM_005612.5	MANE Select	c.899-167A>T		intron	N/A	NP_005603.3
	REST	NM_001193508.2		c.899-167A>T		intron	N/A	NP_001180437.1
	REST	NM_001363453.3		c.899-167A>T		intron	N/A	NP_001350382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	ENST00000309042.12	TSL:1 MANE Select	c.899-167A>T		intron	N/A	ENSP00000311816.7	Q13127-1
	REST	ENST00000514063.2	TSL:1	c.899-167A>T		intron	N/A	ENSP00000501649.1	A0A087X1C2
	REST	ENST00000619101.5	TSL:1	c.899-167A>T		intron	N/A	ENSP00000484836.2	A0A087X1C2

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

African (AFR) AF: 0.252 AC: 10483 AN: 41518

American (AMR) AF: 0.438 AC: 6691 AN: 15262

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

East Asian (EAS) AF: 0.235 AC: 1220 AN: 5182

South Asian (SAS) AF: 0.309 AC: 1489 AN: 4822

European-Finnish (FIN) AF: 0.364 AC: 3849 AN: 10578

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26926 AN: 67984

Other (OTH) AF: 0.364 AC: 768 AN: 2108

Alfa AF: 0.367 Hom.: 1295

Bravo AF: 0.354

Asia WGS AF: 0.247 AC: 860 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.0
DANN	Benign	0.65
PhyloP100		0.16
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: rs10866440; hg19: chr4-57785786;