19-13804879-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001367834.3(ZSWIM4):​c.443G>A​(p.Cys148Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

ZSWIM4
NM_001367834.3 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.67
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZSWIM4NM_001367834.3 linkuse as main transcriptc.443G>A p.Cys148Tyr missense_variant 3/14 ENST00000590508.6 NP_001354763.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZSWIM4ENST00000590508.6 linkuse as main transcriptc.443G>A p.Cys148Tyr missense_variant 3/142 NM_001367834.3 ENSP00000468285 P1
ZSWIM4ENST00000254323.6 linkuse as main transcriptc.443G>A p.Cys148Tyr missense_variant 3/132 ENSP00000254323

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 09, 2022The c.443G>A (p.C148Y) alteration is located in exon 3 (coding exon 3) of the ZSWIM4 gene. This alteration results from a G to A substitution at nucleotide position 443, causing the cysteine (C) at amino acid position 148 to be replaced by a tyrosine (Y). 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
0.97
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Benign
0.047
D
MetaRNN
Pathogenic
0.88
D
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Uncertain
2.8
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-8.5
D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.92
MutPred
0.53
Loss of methylation at K149 (P = 0.0128);
MVP
0.84
MPC
1.0
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.73
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: chr19-13915693; COSMIC: COSV105031433; COSMIC: COSV105031433; API