Genetic Variant ZSWIM4:p.Ile126Thr (chr19-13804813-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001367834.3(ZSWIM4):c.377T>C(p.Ile126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,593,186 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 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

ZSWIM4
NM_001367834.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.69

Variant links:

Genes affected

ZSWIM4 (HGNC:25704): (zinc finger SWIM-type containing 4) Predicted to enable zinc ion binding activity. Predicted to be part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ZSWIM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38335347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM4	NM_001367834.3 link	c.377T>C	p.Ile126Thr	missense_variant	Exon 3 of 14	ENST00000590508.6	NP_001354763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM4	ENST00000590508.6 link	c.377T>C	p.Ile126Thr	missense_variant	Exon 3 of 14	2	NM_001367834.3	ENSP00000468285.2		K7ERJ6
ZSWIM4	ENST00000254323.6 link	c.377T>C	p.Ile126Thr	missense_variant	Exon 3 of 13	2		ENSP00000254323.2		Q9H7M6

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000212

AC:

AN:

240912

Hom.:

AF XY:

0.000207

AC XY:

AN XY:

130414

show subpopulations

Gnomad AFR exome

AF:

0.000186

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:

0.00

Gnomad NFE exome

AF:

0.000431

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.000321

AC:

462

AN:

1441114

Hom.:

Cov.:

AF XY:

0.000317

AC XY:

226

AN XY:

713900

show subpopulations

Gnomad4 AFR exome

AF:

0.0000907

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:

0.000409

Gnomad4 OTH exome

AF:

0.000168

GnomAD4 genome

AF:

0.000132

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000253

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377T>C (p.I126T) alteration is located in exon 3 (coding exon 3) of the ZSWIM4 gene. This alteration results from a T to C substitution at nucleotide position 377, causing the isoleucine (I) at amino acid position 126 to be replaced by a threonine (T). 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

0.90

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.085

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.24

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.69

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.35

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.044

Polyphen

0.13

Vest4

0.58

MVP

0.66

MPC

0.76

ClinPred

0.12

GERP RS

4.6

Varity_R

0.14

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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