Genetic Variant NM_001367799.1:c.803C>A (chr10-73790020-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001367799.1(ZSWIM8):c.803C>A(p.Thr268Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,660 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T268I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZSWIM8
NM_001367799.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.32

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZSWIM8	NM_001367799.1	MANE Select	c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	NP_001354728.1	S4R410
ZSWIM8	NM_001242488.2		c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	NP_001229417.1	A7E2V4-2
ZSWIM8	NM_015037.4		c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	NP_055852.2	A7E2V4-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZSWIM8	ENST00000604729.6	TSL:5 MANE Select	c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	ENSP00000474944.1	S4R410
ZSWIM8	ENST00000605216.5	TSL:1	c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	ENSP00000474748.1	A7E2V4-1
ZSWIM8	ENST00000398706.6	TSL:2	c.803C>A	p.Thr268Lys	missense	Exon 6 of 26	ENSP00000381693.2	A7E2V4-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460660

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111446

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.50

PhyloP100

7.3

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.36

Sift

Benign

0.13

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.79

MutPred

0.42

Gain of methylation at T268 (P = 0.0053)

MVP

0.068

MPC

2.8

ClinPred

0.88

GERP RS

5.3

Varity_R

0.20

gMVP

0.70

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over