10-73792035-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001367799.1(ZSWIM8):c.1496G>T(p.Gly499Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,395,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ZSWIM8
• BP4: Computational evidence support a benign effect (MetaRNN=0.13260558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSWIM8	NM_001367799.1	c.1496G>T	p.Gly499Val	missense_variant	10/26	ENST00000604729.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSWIM8	ENST00000604729.6	c.1496G>T	p.Gly499Val	missense_variant	10/26	5	NM_001367799.1	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395846 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687748

Gnomad4 AFR exome AF: 0.00

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: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.1496G>T (p.G499V) alteration is located in exon 10 (coding exon 10) of the ZSWIM8 gene. This alteration results from a G to T substitution at nucleotide position 1496, causing the glycine (G) at amino acid position 499 to be replaced by a valine (V). 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	0.12
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.0052	T;.;.;.;T
Eigen	Benign	-0.24
Eigen_PC	Benign	0.0036
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.25	.;.;B;.;B
Vest4		0.40
MutPred		0.36		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.043
MPC		1.7
ClinPred		0.45	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.55

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: chr10-75551793;