18-178968-TCTTC-T

Variant names:

• chr18-178968-TCTTC-T
• rs2144233064
• NM_005151.4:c.233_236delTTCC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_005151.4(USP14):​c.233_236delTTCC​(p.Leu78GlnfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USP14 NM_005151.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 7.67
• Publications: 1 publications found

Genes affected

USP14 (HGNC:12612): (ubiquitin specific peptidase 14) This gene encodes a member of the ubiquitin-specific processing (UBP) family of proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. This protein is located in the cytoplasm and cleaves the ubiquitin moiety from ubiquitin-fused precursors and ubiquitinylated proteins. Mice with a mutation that results in reduced expression of the ortholog of this protein are retarded for growth, develop severe tremors by 2 to 3 weeks of age followed by hindlimb paralysis and death by 6 to 10 weeks of age. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

USP14 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-178968-TCTTC-T is Pathogenic according to our data. Variant chr18-178968-TCTTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1064693.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP14	NM_005151.4	c.233_236delTTCC	p.Leu78GlnfsTer11	frameshift_variant	Exon 4 of 16	ENST00000261601.8	NP_005142.1
USP14	NM_001037334.2	c.196-1266_196-1263delTTCC		intron_variant	Intron 3 of 14		NP_001032411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP14	ENST00000261601.8	c.233_236delTTCC	p.Leu78GlnfsTer11	frameshift_variant	Exon 4 of 16	1	NM_005151.4	ENSP00000261601.6

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Distal arthrogryposis and CNS involvement Pathogenic:1

Nov 18, 2021

Istanbul Faculty of Medicine, Istanbul University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Identied in three affected fetuses -

See cases Pathogenic:1

Aug 26, 2022

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PVS1,PM2,PP3,PP5 -

not provided Uncertain:1

Jan 31, 2023

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

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: rs2144233064; hg19: chr18-178968;