6-116660841-C-G

Variant names:

• chr6-116660841-C-G
• rs1219498904
• NM_145062.3:c.565G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145062.3(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. 16/21 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 NM_145062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130
• 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: Likely_benign. The variant received -2 ACMG points.

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

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.565G>C	p.Asp189His	missense	Exon 3 of 10	NP_659499.2	Q96AP4-1
	ZUP1	NM_001361189.2		c.565G>C	p.Asp189His	missense	Exon 3 of 10	NP_001348118.1	Q96AP4-1
	ZUP1	NM_001361190.2		c.61G>C	p.Asp21His	missense	Exon 3 of 10	NP_001348119.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZUP1	ENST00000368576.8	TSL:1 MANE Select	c.565G>C	p.Asp189His	missense	Exon 3 of 10	ENSP00000357565.3	Q96AP4-1
	ZUP1	ENST00000905912.1		c.565G>C	p.Asp189His	missense	Exon 3 of 10	ENSP00000575971.1
	ZUP1	ENST00000935654.1		c.565G>C	p.Asp189His	missense	Exon 3 of 10	ENSP00000605713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.013
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.045
Sift	Benign	0.26	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.28		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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs1219498904; hg19: chr6-116982004;