19-13830635-C-G

Position:

• chr19-13830635-C-G

Variant summary

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

The NM_001367834.3(ZSWIM4):​c.2906C>G​(p.Ser969Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,448,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ZSWIM4 NM_001367834.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

Genes affected

ZSWIM4 (HGNC:25704): (zinc finger SWIM-type containing 4) Predicted to enable zinc ion binding activity. Predicted to be part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

MIR23AHG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZSWIM4	NM_001367834.3	c.2906C>G	p.Ser969Cys	missense_variant	14/14	ENST00000590508.6	NP_001354763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZSWIM4	ENST00000590508.6	c.2906C>G	p.Ser969Cys	missense_variant	14/14	2	NM_001367834.3	ENSP00000468285.2
ZSWIM4	ENST00000254323.6	c.2555C>G	p.Ser852Cys	missense_variant	13/13	2		ENSP00000254323.2
MIR23AHG	ENST00000587762.2	n.12294G>C		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000621 AC: 9 AN: 1448658 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721178

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Jun 03, 2022

The c.2555C>G (p.S852C) alteration is located in exon 13 (coding exon 13) of the ZSWIM4 gene. This alteration results from a C to G substitution at nucleotide position 2555, causing the serine (S) at amino acid position 852 to be replaced by a cysteine (C). 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	0.16
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N;.
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.016	D;D
Polyphen		0.99	D;.
Vest4		0.29
MutPred		0.43		Gain of catalytic residue at L853 (P = 0.0103);.;
MVP		0.53
MPC		0.58
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs1568348728; hg19: chr19-13941449;