4-56910725-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005612.5(REST):c.87C>A(p.Asp29Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D29N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: REST NM_005612.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.417

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31123263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
REST	NM_005612.5	c.87C>A	p.Asp29Glu	missense_variant	2/4	ENST00000309042.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
REST	ENST00000309042.12	c.87C>A	p.Asp29Glu	missense_variant	2/4	1	NM_005612.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.87C>A (p.D29E) alteration is located in exon 2 (coding exon 1) of the REST gene. This alteration results from a C to A substitution at nucleotide position 87, causing the aspartic acid (D) at amino acid position 29 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;.;D;D;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.69	T
Polyphen		1.0	.;.;.;.;.;D;.;D;.
Vest4		0.36, 0.30, 0.66, 0.46, 0.65, 0.30
MutPred		0.41		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.63
MPC		0.89
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.49
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57776891;