10-73790020-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001367799.1(ZSWIM8):c.803C>T(p.Thr268Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

Genes affected

ZSWIM8 (HGNC:23528): (zinc finger SWIM-type containing 8) Enables ubiquitin ligase-substrate adaptor activity. Involved in positive regulation of miRNA catabolic process; proteasome-mediated ubiquitin-dependent protein catabolic process; and protein ubiquitination. Part of Cul3-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZSWIM8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSWIM8	NM_001367799.1	c.803C>T	p.Thr268Ile	missense_variant	6/26	ENST00000604729.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSWIM8	ENST00000604729.6	c.803C>T	p.Thr268Ile	missense_variant	6/26	5	NM_001367799.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460660 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726516

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: 0.00000630

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

Feb 06, 2023

The c.803C>T (p.T268I) alteration is located in exon 6 (coding exon 6) of the ZSWIM8 gene. This alteration results from a C to T substitution at nucleotide position 803, causing the threonine (T) at amino acid position 268 to be replaced by an isoleucine (I). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.088	T;.;.;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
Sift4G	Uncertain	0.039	D;D;D;D;D
Polyphen		1.0	.;.;D;.;D
Vest4		0.81
MutPred		0.36		Loss of phosphorylation at T268 (P = 0.0302);Loss of phosphorylation at T268 (P = 0.0302);Loss of phosphorylation at T268 (P = 0.0302);Loss of phosphorylation at T268 (P = 0.0302);Loss of phosphorylation at T268 (P = 0.0302);
MVP		0.043
MPC		2.7
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs749897485; hg19: chr10-75549778;