10-73799386-C-T

Variant names:

• chr10-73799386-C-T
• rs1238330907
• NM_001367799.1:c.4561C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001367799.1(ZSWIM8):​c.4561C>T​(p.Pro1521Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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]

ZSWIM8-AS1 (HGNC:45103): (ZSWIM8 antisense RNA 1)

ENSG00000272916 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM8	NM_001367799.1	c.4561C>T	p.Pro1521Ser	missense_variant	Exon 21 of 26	ENST00000604729.6	NP_001354728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM8	ENST00000604729.6	c.4561C>T	p.Pro1521Ser	missense_variant	Exon 21 of 26	5	NM_001367799.1	ENSP00000474944.1
ENSG00000272916	ENST00000603027.5	n.*1432+1117G>A		intron_variant	Intron 15 of 16	2		ENSP00000475031.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4546C>T (p.P1516S) alteration is located in exon 21 (coding exon 21) of the ZSWIM8 gene. This alteration results from a C to T substitution at nucleotide position 4546, causing the proline (P) at amino acid position 1516 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T;.;.;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.0	.;.;.;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	.;.;D;.
REVEL	Benign	0.20
Sift	Benign	0.054	.;.;T;.
Sift4G	Benign	0.27	T;T;T;T
Polyphen		1.0, 1.0	.;.;D;D
Vest4		0.75
MutPred		0.28		.;.;.;Loss of catalytic residue at P1516 (P = 0.0019);
MVP		0.082
MPC		1.2
ClinPred		0.92	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.15
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1238330907; hg19: chr10-75559144;