NM_005612.5:c.2865_2866delAA

Variant names:

• chr4-56931722-CAA-C
• rs1553904481
• NM_005612.5:c.2865_2866delAA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005612.5(REST):​c.2865_2866delAA​(p.Asn958SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: REST NM_005612.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.967
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.13 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-56931722-CAA-C is Pathogenic according to our data. Variant chr4-56931722-CAA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427771.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	NM_005612.5	MANE Select	c.2865_2866delAA	p.Asn958SerfsTer9	frameshift	Exon 4 of 4	NP_005603.3
	REST	NM_001193508.2		c.2865_2866delAA	p.Asn958SerfsTer9	frameshift	Exon 4 of 4	NP_001180437.1
	REST	NM_001363453.3		c.2865_2866delAA	p.Asn958SerfsTer9	frameshift	Exon 4 of 4	NP_001350382.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	REST	ENST00000309042.12	TSL:1 MANE Select	c.2865_2866delAA	p.Asn958SerfsTer9	frameshift	Exon 4 of 4	ENSP00000311816.7
	REST	ENST00000514063.2	TSL:1	c.*1892_*1893delAA		3_prime_UTR	Exon 5 of 5	ENSP00000501649.1
	REST	ENST00000619101.5	TSL:1	c.*1892_*1893delAA		3_prime_UTR	Exon 5 of 5	ENSP00000484836.2

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Fibromatosis, gingival, 1 (1)
1	-	-	Fibromatosis, gingival, 5 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=12/188	disease causing (ClinVar)

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: rs1553904481; hg19: chr4-57797888;