Genetic Variant ZSWIM8:p.Tyr1128His (chr10-73797220-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001367799.1(ZSWIM8):c.3382T>C(p.Tyr1128His) variant causes a missense change. The variant allele was found at a frequency of 0.000191 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

ZSWIM8
NM_001367799.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.90

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29462087).

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM8	NM_001367799.1 link	c.3382T>C	p.Tyr1128His	missense_variant	Exon 17 of 26	ENST00000604729.6	NP_001354728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZSWIM8	ENST00000604729.6 link	c.3382T>C	p.Tyr1128His	missense_variant	Exon 17 of 26	5	NM_001367799.1	ENSP00000474944.1	S4R410
ENSG00000272916	ENST00000603027.5 link	n.*2040A>G		non_coding_transcript_exon_variant	Exon 17 of 17	2		ENSP00000475031.1	S4R438
ENSG00000272916	ENST00000603027.5 link	n.*2040A>G		3_prime_UTR_variant	Exon 17 of 17	2		ENSP00000475031.1	S4R438

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

249062

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135154

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000196

AC:

287

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

145

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000240

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000144

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000282

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3367T>C (p.Y1123H) alteration is located in exon 17 (coding exon 17) of the ZSWIM8 gene. This alteration results from a T to C substitution at nucleotide position 3367, causing the tyrosine (Y) at amino acid position 1123 to be replaced by a histidine (H). 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

Uncertain

0.44

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

T;.;.;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.7

.;.;.;.;L

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.96

.;.;N;.;.

REVEL

Benign

0.13

Sift

Benign

0.038

.;.;D;.;.

Sift4G

Benign

0.56

T;T;T;T;T

Polyphen

1.0

.;.;D;.;D

Vest4

0.79

MVP

0.043

MPC

2.1

ClinPred

0.16

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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