10-73797154-G-T

Variant names:

• chr10-73797154-G-T
• rs763410056
• NM_001367799.1:c.3316G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367799.1(ZSWIM8):​c.3316G>T​(p.Ala1106Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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

ENSG00000272916 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1353873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM8	NM_001367799.1	c.3316G>T	p.Ala1106Ser	missense_variant	Exon 17 of 26	ENST00000604729.6	NP_001354728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM8	ENST00000604729.6	c.3316G>T	p.Ala1106Ser	missense_variant	Exon 17 of 26	5	NM_001367799.1	ENSP00000474944.1
ENSG00000272916	ENST00000603027.5	n.*2106C>A		non_coding_transcript_exon_variant	Exon 17 of 17	2		ENSP00000475031.1
ENSG00000272916	ENST00000603027.5	n.*2106C>A		3_prime_UTR_variant	Exon 17 of 17	2		ENSP00000475031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248584 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134912

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: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3301G>T (p.A1101S) alteration is located in exon 17 (coding exon 17) of the ZSWIM8 gene. This alteration results from a G to T substitution at nucleotide position 3301, causing the alanine (A) at amino acid position 1101 to be replaced by a serine (S). 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	0.082
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0066	T;.;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	.;.;.;.;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.10	.;.;N;.;.
REVEL	Benign	0.062
Sift	Benign	0.40	.;.;T;.;.
Sift4G	Benign	0.80	T;T;T;T;T
Polyphen		0.0090	.;.;B;.;B
Vest4		0.37
MutPred		0.071		.;.;.;Gain of phosphorylation at A1101 (P = 0.0311);Gain of phosphorylation at A1101 (P = 0.0311);
MVP		0.043
MPC		0.73
ClinPred		0.22	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.11
gMVP		0.18

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

Other links and lift over

dbSNP: rs763410056; hg19: chr10-75556912;