4-56931247-CCA-TTG

Variant names:

• chr4-56931247-CCA-TTG
• NM_005612.5:c.2389_2391delCCAinsTTG
• REST p.Pro797Leu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005612.5(REST):​c.2389_2391delCCAinsTTG​(p.Pro797Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P797P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: REST NM_005612.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.2389_2391delCCAinsTTG	p.Pro797Leu	missense	N/A	NP_005603.3
	REST	NM_001193508.2		c.2389_2391delCCAinsTTG	p.Pro797Leu	missense	N/A	NP_001180437.1
	REST	NM_001363453.3		c.2389_2391delCCAinsTTG	p.Pro797Leu	missense	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.2389_2391delCCAinsTTG	p.Pro797Leu	missense	N/A	ENSP00000311816.7	Q13127-1
	REST	ENST00000514063.2	TSL:1	c.*1416_*1418delCCAinsTTG		3_prime_UTR	Exon 5 of 5	ENSP00000501649.1	A0A087X1C2
	REST	ENST00000619101.5	TSL:1	c.*1416_*1418delCCAinsTTG		3_prime_UTR	Exon 5 of 5	ENSP00000484836.2	A0A087X1C2

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.025

Splicing

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

hg19: chr4-57797413;