19-13830299-G-A

Position:

• chr19-13830299-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001367834.3(ZSWIM4):​c.2570G>A​(p.Arg857Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZSWIM4 NM_001367834.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.51

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZSWIM4	NM_001367834.3	c.2570G>A	p.Arg857Gln	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.2570G>A	p.Arg857Gln	missense_variant	14/14	2	NM_001367834.3	ENSP00000468285.2
ZSWIM4	ENST00000254323.6	c.2219G>A	p.Arg740Gln	missense_variant	13/13	2		ENSP00000254323.2
ZSWIM4	ENST00000592227.1	c.602G>A	p.Arg201Gln	missense_variant	5/5	3		ENSP00000465180.1
MIR23AHG	ENST00000587762.2	n.12630C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727076

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 15, 2021

The c.2219G>A (p.R740Q) alteration is located in exon 13 (coding exon 13) of the ZSWIM4 gene. This alteration results from a G to A substitution at nucleotide position 2219, causing the arginine (R) at amino acid position 740 to be replaced by a glutamine (Q). 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	0.12
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.26
Sift	Benign	0.10	T;.
Sift4G	Benign	0.10	T;D
Polyphen		0.94	P;.
Vest4		0.61
MutPred		0.54		Gain of helix (P = 0.0854);.;
MVP		0.61
MPC		0.69
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.31
gMVP		0.71

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: rs1410482866; hg19: chr19-13941113; COSMIC: COSV54324528; COSMIC: COSV54324528;