10-73799017-G-A

Variant names:

• chr10-73799017-G-A
• NM_001367799.1:c.4192G>A

Variant summary

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

The NM_001367799.1(ZSWIM8):​c.4192G>A​(p.Glu1398Lys) 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: 32)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.49

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.4192G>A	p.Glu1398Lys	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.4192G>A	p.Glu1398Lys	missense_variant	Exon 21 of 26	5	NM_001367799.1	ENSP00000474944.1
ENSG00000272916	ENST00000603027.5	n.*1433-958C>T		intron_variant	Intron 15 of 16	2		ENSP00000475031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4177G>A (p.E1393K) alteration is located in exon 21 (coding exon 21) of the ZSWIM8 gene. This alteration results from a G to A substitution at nucleotide position 4177, causing the glutamic acid (E) at amino acid position 1393 to be replaced by a lysine (K). 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	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	.;.;D;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0060	.;.;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	.;.;D;.;D
Vest4		0.83
MutPred		0.48		.;.;.;Gain of ubiquitination at E1393 (P = 0.0114);Gain of ubiquitination at E1393 (P = 0.0114);
MVP		0.20
MPC		1.3
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.55
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-75558775;