6-116656843-C-T

Variant names:

• chr6-116656843-C-T
• NM_145062.3:c.802G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 3 ACMG points.

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

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.802G>A	p.Gly268Ser	missense	Exon 5 of 10	NP_659499.2	Q96AP4-1
	ZUP1	NM_001361189.2		c.802G>A	p.Gly268Ser	missense	Exon 5 of 10	NP_001348118.1	Q96AP4-1
	ZUP1	NM_001361190.2		c.298G>A	p.Gly100Ser	missense	Exon 5 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.802G>A	p.Gly268Ser	missense	Exon 5 of 10	ENSP00000357565.3	Q96AP4-1
	ZUP1	ENST00000905912.1		c.802G>A	p.Gly268Ser	missense	Exon 5 of 10	ENSP00000575971.1
	ZUP1	ENST00000935654.1		c.802G>A	p.Gly268Ser	missense	Exon 5 of 10	ENSP00000605713.1

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

African (AFR) AF: 0.00 AC: 0 AN: 32600

American (AMR) AF: 0.00 AC: 0 AN: 41980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00 AC: 0 AN: 39130

South Asian (SAS) AF: 0.00 AC: 0 AN: 83438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101510

Other (OTH) AF: 0.00 AC: 0 AN: 59684

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	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
PhyloP100		7.2
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
Mutation Taster		=49/51	disease causing

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

Other links and lift over

hg19: chr6-116978006;