19-12526568-A-T

Variant names:

• chr19-12526568-A-T
• NM_144976.4:c.1540T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144976.4(ZNF564):​c.1540T>A​(p.Phe514Ile) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF564 NM_144976.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 publications found

Genes affected

ZNF564 (HGNC:31106): (zinc finger protein 564) Predicted to enable DNA-binding transcription factor activity 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 nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000269693 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF564	NM_144976.4	c.1540T>A	p.Phe514Ile	missense_variant	Exon 4 of 4	ENST00000339282.12	NP_659413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF564	ENST00000339282.12	c.1540T>A	p.Phe514Ile	missense_variant	Exon 4 of 4	1	NM_144976.4	ENSP00000340004.6
ENSG00000269693	ENST00000593682.1	n.*4518T>A		non_coding_transcript_exon_variant	Exon 4 of 4	1		ENSP00000473043.1
ENSG00000269693	ENST00000593682.1	n.*4518T>A		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000473043.1
ENSG00000196826	ENST00000428311.1	c.3+24762T>A		intron_variant	Intron 1 of 3	2		ENSP00000404127.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1540T>A (p.F514I) alteration is located in exon 4 (coding exon 4) of the ZNF564 gene. This alteration results from a T to A substitution at nucleotide position 1540, causing the phenylalanine (F) at amino acid position 514 to be replaced by an isoleucine (I). 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	0.92
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0076	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		3.0
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.76		Gain of ubiquitination at K512 (P = 0.0704);
MVP		0.56
MPC		0.79
ClinPred		0.97	D
GERP RS		1.7
Varity_R		0.58
gMVP		0.069
Mutation Taster		=97/3	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: chr19-12637382;