19-56423803-G-T

Variant names:

• chr19-56423803-G-T
• NM_152478.3:c.1145G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152478.3. 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
	ZNF583	NM_152478.3	MANE Select	c.1145G>T	p.Cys382Phe	missense	Exon 5 of 5	NP_689691.2	Q96ND8
	ZNF583	NM_001159860.2		c.1145G>T	p.Cys382Phe	missense	Exon 5 of 5	NP_001153332.1	Q96ND8
	ZNF583	NM_001159861.2		c.1145G>T	p.Cys382Phe	missense	Exon 5 of 5	NP_001153333.1	Q96ND8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF583	ENST00000333201.13	TSL:2 MANE Select	c.1145G>T	p.Cys382Phe	missense	Exon 5 of 5	ENSP00000388502.2	Q96ND8
	ZNF583	ENST00000585612.1	TSL:1	n.653+1G>T		splice_donor intron	N/A
	ZNF583	ENST00000890730.1		c.1148G>T	p.Cys383Phe	missense	Exon 5 of 5	ENSP00000560789.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	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
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
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.62		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
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

hg19: chr19-56935172;