19-56423803-G-T

Position:

• chr19-56423803-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152478.3(ZNF583):​c.1145G>T​(p.Cys382Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF583 NM_152478.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.89

Genes affected

ZNF583 (HGNC:26427): (zinc finger protein 583) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF583	NM_152478.3	c.1145G>T	p.Cys382Phe	missense_variant	5/5	ENST00000333201.13	NP_689691.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF583	ENST00000333201.13	c.1145G>T	p.Cys382Phe	missense_variant	5/5	2	NM_152478.3	ENSP00000388502	P1
ZNF583	ENST00000585612.1	n.653+1G>T		splice_donor_variant, non_coding_transcript_variant		1
ZNF583	ENST00000291598.11	c.1145G>T	p.Cys382Phe	missense_variant	5/5	3		ENSP00000291598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 05, 2021

The c.1145G>T (p.C382F) alteration is located in exon 5 (coding exon 4) of the ZNF583 gene. This alteration results from a G to T substitution at nucleotide position 1145, causing the cysteine (C) at amino acid position 382 to be replaced by a phenylalanine (F). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.61	T;.
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.62		Loss of ubiquitination at K387 (P = 0.0637);Loss of ubiquitination at K387 (P = 0.0637);
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.95
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-56935172;