19-52511241-A-T

Position:

• chr19-52511241-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099694.2(ZNF578):​c.860A>T​(p.Tyr287Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF578 NM_001099694.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.726

Genes affected

ZNF578 (HGNC:26449): (zinc finger protein 578) 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 located in cytoplasm. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269349 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09577763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF578	NM_001099694.2	c.860A>T	p.Tyr287Phe	missense_variant	6/6	ENST00000421239.7	NP_001093164.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF578	ENST00000421239.7	c.860A>T	p.Tyr287Phe	missense_variant	6/6	2	NM_001099694.2	ENSP00000459216.1
ENSG00000269349	ENST00000599143.1	n.*41T>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Aug 14, 2024

The c.860A>T (p.Y287F) alteration is located in exon 6 (coding exon 3) of the ZNF578 gene. This alteration results from a A to T substitution at nucleotide position 860, causing the tyrosine (Y) at amino acid position 287 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	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.15	N
Sift4G	Benign	0.070	T
Vest4		0.15
MVP		0.099
MPC		0.15
ClinPred		0.94	D
GERP RS		1.3
Varity_R		0.28
gMVP		0.0054

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: rs1350948868; hg19: chr19-53014494;