rs4109037

Variant names:

• chr4-56909443-T-A
• rs4109037
• NM_005612.5:c.-9-1187T>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.-9-1187T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,338 control chromosomes in the GnomAD database, including 1,096 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 0.10 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: REST NM_005612.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.582
• Publications: 6 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=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
REST	NM_005612.5	c.-9-1187T>A		intron_variant	Intron 1 of 3	ENST00000309042.12	NP_005603.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
REST	ENST00000309042.12	c.-9-1187T>A		intron_variant	Intron 1 of 3	1	NM_005612.5	ENSP00000311816.7

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15924 AN: 152150 Hom.: 1098 Cov.: 33

Gnomad AFR AF: 0.0263

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0993

Gnomad FIN AF: 0.0940

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.129 AC: 9 AN: 70 Hom.: 0 Cov.: 0 AF XY: 0.130 AC XY: 7 AN XY: 54

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 1 AN: 2

European-Finnish (FIN) AF: 0.250 AC: 3 AN: 12

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0952 AC: 4 AN: 42

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.105 AC: 15917 AN: 152268 Hom.: 1096 Cov.: 33 AF XY: 0.103 AC XY: 7681 AN XY: 74448

African (AFR) AF: 0.0262 AC: 1091 AN: 41572

American (AMR) AF: 0.114 AC: 1747 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5170

South Asian (SAS) AF: 0.100 AC: 482 AN: 4822

European-Finnish (FIN) AF: 0.0940 AC: 997 AN: 10612

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10595 AN: 68016

Other (OTH) AF: 0.129 AC: 273 AN: 2116

Alfa AF: 0.128 Hom.: 184

Bravo AF: 0.103

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.79
PhyloP100		0.58
PromoterAI		-0.030	Neutral
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: rs4109037; hg19: chr4-57775609; COSMIC: COSV58361959;