Genetic Variant ZNF564:p.Ile441Met (chr19-12526785-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144976.4(ZNF564):c.1323A>G(p.Ile441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZNF564
NM_144976.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.79

Variant links:

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]

ZNF564 links:

ENSG00000196826 (HGNC:):

ENSG00000196826 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06069064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF564	NM_144976.4 link	c.1323A>G	p.Ile441Met	missense_variant	Exon 4 of 4	ENST00000339282.12	NP_659413.1	Q8TBZ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF564	ENST00000339282.12 link	c.1323A>G	p.Ile441Met	missense_variant	Exon 4 of 4	1	NM_144976.4	ENSP00000340004.6	Q8TBZ8
ENSG00000196826	ENST00000428311.1 link	c.3+24545A>G		intron_variant	Intron 1 of 3	2		ENSP00000404127.1
ENSG00000269693	ENST00000593682.1 link	n.*4301A>G		non_coding_transcript_exon_variant	Exon 4 of 4	1		ENSP00000473043.1	M0R378
ENSG00000269693	ENST00000593682.1 link	n.*4301A>G		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000473043.1	M0R378

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1323A>G (p.I441M) alteration is located in exon 4 (coding exon 4) of the ZNF564 gene. This alteration results from a A to G substitution at nucleotide position 1323, causing the isoleucine (I) at amino acid position 441 to be replaced by a methionine (M). 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

0.19

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.9

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.020

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0

LIST_S2

Benign

0.23

M_CAP

Benign

0.0013

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

PhyloP100

-4.8

PROVEAN

Benign

1.5

REVEL

Benign

0.080

Sift

Benign

0.030

Sift4G

Uncertain

0.055

Polyphen

0.036

Vest4

0.086

MutPred

0.50

Gain of disorder (P = 0.0704);

MVP

0.16

MPC

0.44

ClinPred

0.23

GERP RS

0.68

Varity_R

0.10

gMVP

0.014

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over