Genetic Variant ZNF569:p.Met254Leu (chr19-37413898-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152484.3(ZNF569):c.760A>C(p.Met254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000021 ( 0 hom. )

Consequence

ZNF569
NM_152484.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0260

Publications

0 publications found

Variant links:

Genes affected

ZNF569 (HGNC:24737): (zinc finger protein 569) 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]

ZNF569 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08181125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF569	NM_152484.3 link	c.760A>C	p.Met254Leu	missense_variant	Exon 6 of 6	ENST00000316950.11	NP_689697.2	Q5MCW4-1A0A024R0G4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF569	ENST00000316950.11 link	c.760A>C	p.Met254Leu	missense_variant	Exon 6 of 6	1	NM_152484.3	ENSP00000325018.5	Q5MCW4-1
ZNF569	ENST00000392149.6 link	c.760A>C	p.Met254Leu	missense_variant	Exon 5 of 5	1		ENSP00000375992.2	Q5MCW4-1
ZNF569	ENST00000392150.2 link	c.283A>C	p.Met95Leu	missense_variant	Exon 2 of 2	1		ENSP00000375993.2	Q5MCW4-2
ZNF569	ENST00000448051.7 link	c.832A>C	p.Met278Leu	missense_variant	Exon 9 of 9	2		ENSP00000466221.2	K7ELU1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461098

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.760A>C (p.M254L) alteration is located in exon 6 (coding exon 4) of the ZNF569 gene. This alteration results from a A to C substitution at nucleotide position 760, causing the methionine (M) at amino acid position 254 to be replaced by a leucine (L). 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

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.2

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.049

T;T;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.00015

LIST_S2

Benign

0.21

.;T;T

M_CAP

Benign

0.0033

MetaRNN

Benign

0.082

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.28

N;N;.

PhyloP100

-0.026

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.069

Sift

Uncertain

0.028

.;D;T

Sift4G

Benign

0.70

T;T;T

Polyphen

0.025

B;B;.

Vest4

0.32

MutPred

0.42

Loss of MoRF binding (P = 0.0866);Loss of MoRF binding (P = 0.0866);.;

MVP

0.33

MPC

0.12

ClinPred

0.18

GERP RS

1.6

Varity_R

0.26

gMVP

0.027

Mutation Taster

=94/6

polymorphism

(source)

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

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19-37413898-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over