chr6-116652072-C-A

Variant names:

• chr6-116652072-C-A
• rs764239824
• NM_145062.3:c.1082G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_145062.3(ZUP1):​c.1082G>T​(p.Gly361Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,722 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: 0.000013 (0 hom.)
• Consequence: ZUP1 NM_145062.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

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.1082G>T	p.Gly361Val	missense	Exon 6 of 10	NP_659499.2	Q96AP4-1
	ZUP1	NM_001361189.2		c.1082G>T	p.Gly361Val	missense	Exon 6 of 10	NP_001348118.1	Q96AP4-1
	ZUP1	NM_001361190.2		c.578G>T	p.Gly193Val	missense	Exon 6 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.1082G>T	p.Gly361Val	missense	Exon 6 of 10	ENSP00000357565.3	Q96AP4-1
	ZUP1	ENST00000905912.1		c.1082G>T	p.Gly361Val	missense	Exon 6 of 10	ENSP00000575971.1
	ZUP1	ENST00000935654.1		c.1082G>T	p.Gly361Val	missense	Exon 6 of 10	ENSP00000605713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251310 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

ExAC AF: 0.0000165 AC: 2

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.14	T
PhyloP100		7.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		Loss of helix (P = 0.0104)
MVP		0.83
MPC		0.45
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.86
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs764239824; hg19: chr6-116973235;