10-73799245-A-G

Variant names:

• chr10-73799245-A-G
• rs1334777399
• NM_001367799.1:c.4420A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367799.1(ZSWIM8):​c.4420A>G​(p.Thr1474Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 6.9e-7 (0 hom.)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14148256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367799.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM8	NM_001367799.1	MANE Select	c.4420A>G	p.Thr1474Ala	missense	Exon 21 of 26	NP_001354728.1	S4R410
	ZSWIM8	NM_001242488.2		c.4405A>G	p.Thr1469Ala	missense	Exon 21 of 26	NP_001229417.1	A7E2V4-2
	ZSWIM8	NM_015037.4		c.4420A>G	p.Thr1474Ala	missense	Exon 21 of 26	NP_055852.2	A7E2V4-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM8	ENST00000604729.6	TSL:5 MANE Select	c.4420A>G	p.Thr1474Ala	missense	Exon 21 of 26	ENSP00000474944.1	S4R410
	ZSWIM8	ENST00000605216.5	TSL:1	c.4405A>G	p.Thr1469Ala	missense	Exon 21 of 26	ENSP00000474748.1	A7E2V4-1
	ZSWIM8	ENST00000603187.5	TSL:1	c.2422A>G	p.Thr808Ala	missense	Exon 12 of 17	ENSP00000474766.1	S4R3U7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450592 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 720594

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 42620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39174

South Asian (SAS) AF: 0.00 AC: 0 AN: 84842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106880

Other (OTH) AF: 0.00 AC: 0 AN: 59908

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0091	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.033
Sift	Benign	0.44	T
Sift4G	Benign	0.78	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.043
MPC		0.42
ClinPred		0.44	T
GERP RS		5.7
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.20
gMVP		0.27
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1334777399; hg19: chr10-75559003;