chr4-56930734-G-A

Variant names:

• chr4-56930734-G-A
• rs2228991
• NM_005612.5:c.1876G>A
• REST p.Val626Ile

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.1876G>A​(p.Val626Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0546 in 1,601,638 control chromosomes in the GnomAD database, including 4,711 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V626L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.087 (877 hom., cov: 33)
  • Exomes 𝑓: 0.051 (3834 hom.)
• Consequence: REST NM_005612.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.09
• Publications: 17 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, Labcorp Genetics (formerly Invitae), G2P
• 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 (MetaRNN=0.005392164).
• BP6: Variant 4-56930734-G-A is Benign according to our data. Variant chr4-56930734-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.205 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.1876G>A	p.Val626Ile	missense	Exon 4 of 4	NP_005603.3
	REST	NM_001193508.2		c.1876G>A	p.Val626Ile	missense	Exon 4 of 4	NP_001180437.1
	REST	NM_001363453.3		c.1876G>A	p.Val626Ile	missense	Exon 4 of 4	NP_001350382.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	ENST00000309042.12	TSL:1 MANE Select	c.1876G>A	p.Val626Ile	missense	Exon 4 of 4	ENSP00000311816.7	Q13127-1
	REST	ENST00000514063.2	TSL:1	c.*903G>A		3_prime_UTR	Exon 5 of 5	ENSP00000501649.1	A0A087X1C2
	REST	ENST00000619101.5	TSL:1	c.*903G>A		3_prime_UTR	Exon 5 of 5	ENSP00000484836.2	A0A087X1C2

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13167 AN: 152068 Hom.: 870 Cov.: 33

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.0711

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0793

GnomAD2 exomes AF: 0.0887 AC: 20960 AN: 236230 AF XY: 0.0768

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.272

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.223

Gnomad FIN exome AF: 0.0739

Gnomad NFE exome AF: 0.0392

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0512 AC: 74225 AN: 1449452 Hom.: 3834 Cov.: 33 AF XY: 0.0488 AC XY: 35150 AN XY: 720890

African (AFR) AF: 0.128 AC: 4162 AN: 32558

American (AMR) AF: 0.262 AC: 10699 AN: 40812

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 412 AN: 25274

East Asian (EAS) AF: 0.203 AC: 8057 AN: 39648

South Asian (SAS) AF: 0.0120 AC: 1006 AN: 84140

European-Finnish (FIN) AF: 0.0695 AC: 3687 AN: 53056

Middle Eastern (MID) AF: 0.0163 AC: 92 AN: 5650

European-Non Finnish (NFE) AF: 0.0385 AC: 42683 AN: 1108592

Other (OTH) AF: 0.0574 AC: 3427 AN: 59722

GnomAD4 genome AF: 0.0866 AC: 13177 AN: 152186 Hom.: 877 Cov.: 33 AF XY: 0.0889 AC XY: 6617 AN XY: 74406

African (AFR) AF: 0.124 AC: 5144 AN: 41526

American (AMR) AF: 0.194 AC: 2971 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.215 AC: 1108 AN: 5148

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4822

European-Finnish (FIN) AF: 0.0711 AC: 754 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0425 AC: 2888 AN: 68014

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

Alfa AF: 0.0428 Hom.: 174

Bravo AF: 0.102

Asia WGS AF: 0.108 AC: 374 AN: 3478

EpiCase AF: 0.0325

EpiControl AF: 0.0333

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.55
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.69	N
PhyloP100		-1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.016
Sift	Benign	0.24	T
Sift4G	Benign	0.27	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.0091
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2228991;

hg19: chr4-57796900;

COSMIC: COSV107357641;

COSMIC: COSV107357641;