6-116660841-C-G

Position:

• chr6-116660841-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000368576.8(ZUP1):​c.565G>C​(p.Asp189His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 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)
• Consequence: ZUP1 ENST00000368576.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.066975296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZUP1	NM_145062.3	c.565G>C	p.Asp189His	missense_variant	3/10	ENST00000368576.8	NP_659499.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZUP1	ENST00000368576.8	c.565G>C	p.Asp189His	missense_variant	3/10	1	NM_145062.3	ENSP00000357565	P1
ZUP1	ENST00000368573.5	c.565G>C	p.Asp189His	missense_variant	3/5	5		ENSP00000357562
ZUP1	ENST00000471919.1	n.514G>C		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

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

Jul 27, 2021

The c.565G>C (p.D189H) alteration is located in exon 3 (coding exon 2) of the ZUFSP gene. This alteration results from a G to C substitution at nucleotide position 565, causing the aspartic acid (D) at amino acid position 189 to be replaced by a histidine (H). 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	0.077
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0071	T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.045
Sift	Benign	0.26	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0020	B;.
Vest4		0.10
MutPred		0.28		Loss of sheet (P = 0.1907);Loss of sheet (P = 0.1907);
MVP		0.33
MPC		0.14
ClinPred		0.095	T
GERP RS		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr6-116982004;