Genetic Variant ZUP1:p.Val495Ile (chr6-116645920-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145062.3(ZUP1):c.1483G>A(p.Val495Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZUP1
NM_145062.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0610

Variant links:

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]

ZUP1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07581085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZUP1	NM_145062.3 link	c.1483G>A	p.Val495Ile	missense_variant	Exon 9 of 10	ENST00000368576.8	NP_659499.2	Q96AP4-1A0A0S2Z644

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZUP1	ENST00000368576.8 link	c.1483G>A	p.Val495Ile	missense_variant	Exon 9 of 10	1	NM_145062.3	ENSP00000357565.3		Q96AP4-1
ZUP1	ENST00000485498.1 link	n.339G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250226

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460336

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726468

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1483G>A (p.V495I) alteration is located in exon 9 (coding exon 8) of the ZUFSP gene. This alteration results from a G to A substitution at nucleotide position 1483, causing the valine (V) at amino acid position 495 to be replaced by an isoleucine (I). 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

Benign

0.063

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.75

CADD

Benign

3.6

DANN

Benign

0.83

DEOGEN2

Benign

0.032

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.80

M_CAP

Benign

0.0035

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.30

PROVEAN

Benign

0.23

REVEL

Benign

0.032

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.13

MutPred

0.57

Loss of sheet (P = 0.0104);

MVP

0.11

MPC

0.056

ClinPred

0.069

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over