6-116656843-C-T

Position:

• chr6-116656843-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145062.3(ZUP1):​c.802G>A​(p.Gly268Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZUP1 NM_145062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZUP1	NM_145062.3	c.802G>A	p.Gly268Ser	missense_variant	5/10	ENST00000368576.8	NP_659499.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZUP1	ENST00000368576.8	c.802G>A	p.Gly268Ser	missense_variant	5/10	1	NM_145062.3	ENSP00000357565.3
ZUP1	ENST00000368573.5	c.792+1960G>A		intron_variant		5		ENSP00000357562.1
ZUP1	ENST00000471919.1	n.888G>A		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442548 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 717696

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.802G>A (p.G268S) alteration is located in exon 5 (coding exon 4) of the ZUFSP gene. This alteration results from a G to A substitution at nucleotide position 802, causing the glycine (G) at amino acid position 268 to be replaced by a serine (S). 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	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.087	T
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.45		Gain of loop (P = 0.0079);
MVP		0.81
MPC		0.40
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.90
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-116978006;