Genetic Variant ZSWIM8:p.Gly1464Asp (chr10-73799216-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001367799.1(ZSWIM8):c.4391G>A(p.Gly1464Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,606,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ZSWIM8
NM_001367799.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.77

Variant links:

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 links:

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

ZSWIM8-AS1 links:

ENSG00000272916 (HGNC:):

ENSG00000272916 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.040595084).

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM8	NM_001367799.1 link	c.4391G>A	p.Gly1464Asp	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 link	c.4391G>A	p.Gly1464Asp	missense_variant	Exon 21 of 26	5	NM_001367799.1	ENSP00000474944.1		S4R410
ENSG00000272916	ENST00000603027.5 link	n.*1433-1157C>T		intron_variant	Intron 15 of 16	2		ENSP00000475031.1		S4R438

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000514

AC:

AN:

233606

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

126542

show subpopulations

Gnomad AFR exome

AF:

0.000718

Gnomad AMR exome

AF:

0.0000309

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1454530

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

722828

show subpopulations

Gnomad4 AFR exome

AF:

0.000779

Gnomad4 AMR exome

AF:

0.0000462

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000217

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000773

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.000975

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4376G>A (p.G1459D) 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 4376, causing the glycine (G) at amino acid position 1459 to be replaced by an aspartic acid (D). 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

0.17

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;.;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.0061

MetaRNN

Benign

0.041

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

.;.;.;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.61

.;.;N;.

REVEL

Benign

0.084

Sift

Uncertain

0.028

.;.;D;.

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.25

.;.;B;B

Vest4

0.32

MVP

0.043

MPC

0.56

ClinPred

0.041

GERP RS

5.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.16

gMVP

0.29

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over