6-116645732-AAG-CAC

Variant names:

• chr6-116645732-AAG-CAC
• NM_145062.3:c.1669_1671delCTTinsGTG
• ZUP1 p.Leu557Val

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_145062.3(ZUP1):​c.1669_1671delCTTinsGTG​(p.Leu557Val) variant causes a missense change involving the alteration of a 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 Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZUP1 NM_145062.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.34
• Publications: 0 publications found

Genes affected

ZUP1 (HGNC:21224): (zinc finger containing ubiquitin peptidase 1) This gene encodes a protein containing zinc finger motifs and a cysteine peptidase domain. The encoded protein functions as a K63-specific de-ubiquitinating enzyme that specifically cleaves long K63-linked polyubiquitin chains in the middle of a chain (i.e. "endo cleavage) rather than by removing the terminal ubiquitin from a chain. This enzyme is thought to be involved in the regulation of DNA repair by cleaving K63-linked ubiquitin chains at repair foci. This protein is related to proteases for the ubiquitin-like modifiers Ufm1 (ubiquitin fold modifier 1) and Atg8/Gabarapl2, but does not have any activity on these modifiers. [provided by RefSeq, Mar 2018]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145062.3. 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
	ZUP1	NM_145062.3	MANE Select	c.1669_1671delCTTinsGTG	p.Leu557Val	missense	N/A	NP_659499.2	Q96AP4-1
	ZUP1	NM_001361189.2		c.1669_1671delCTTinsGTG	p.Leu557Val	missense	N/A	NP_001348118.1	Q96AP4-1
	ZUP1	NM_001361190.2		c.1165_1167delCTTinsGTG	p.Leu389Val	missense	N/A	NP_001348119.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZUP1	ENST00000368576.8	TSL:1 MANE Select	c.1669_1671delCTTinsGTG	p.Leu557Val	missense	N/A	ENSP00000357565.3	Q96AP4-1
	ZUP1	ENST00000905912.1		c.1669_1671delCTTinsGTG	p.Leu557Val	missense	N/A	ENSP00000575971.1
	ZUP1	ENST00000935654.1		c.1669_1671delCTTinsGTG	p.Leu557Val	missense	N/A	ENSP00000605713.1

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3

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: chr6-116966895;