chr10-73798446-A-G

Variant names:

• chr10-73798446-A-G
• rs755396903
• NM_001367799.1:c.4169A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001367799.1(ZSWIM8):​c.4169A>G​(p.Lys1390Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,612,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ZSWIM8 NM_001367799.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.80
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23721632).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.4169A>G	p.Lys1390Arg	missense	Exon 20 of 26	NP_001354728.1	S4R410
	ZSWIM8	NM_001242488.2		c.4154A>G	p.Lys1385Arg	missense	Exon 20 of 26	NP_001229417.1	A7E2V4-2
	ZSWIM8	NM_015037.4		c.4169A>G	p.Lys1390Arg	missense	Exon 20 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.4169A>G	p.Lys1390Arg	missense	Exon 20 of 26	ENSP00000474944.1	S4R410
	ZSWIM8	ENST00000605216.5	TSL:1	c.4154A>G	p.Lys1385Arg	missense	Exon 20 of 26	ENSP00000474748.1	A7E2V4-1
	ZSWIM8	ENST00000603187.5	TSL:1	c.2171A>G	p.Lys724Arg	missense	Exon 11 of 17	ENSP00000474766.1	S4R3U7

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000283 AC: 7 AN: 246982 AF XY: 0.0000373

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459784 Hom.: 0 Cov.: 31 AF XY: 0.0000207 AC XY: 15 AN XY: 725748

African (AFR) AF: 0.0000897 AC: 3 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1110330

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

African (AFR) AF: 0.0000965 AC: 4 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

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	0.24
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.22
Sift	Benign	0.14	T
Sift4G	Benign	0.083	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.24		Loss of methylation at K1385 (P = 0.0038)
MVP		0.14
MPC		0.70
ClinPred		0.22	T
GERP RS		5.4
Varity_R		0.31
gMVP		0.66
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs755396903; hg19: chr10-75558204;