Genetic Variant ZNF565:p.Arg355Ile (chr19-36182902-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_152477.5(ZNF565):c.1064G>T(p.Arg355Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ZNF565
NM_152477.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.746

Variant links:

Genes affected

ZNF565 (HGNC:26726): (zinc finger protein 565) 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]

ZNF565 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26382965).

BS2

High AC in GnomAdExome4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF565	NM_152477.5 link	c.1064G>T	p.Arg355Ile	missense_variant	Exon 5 of 5	ENST00000304116.10	NP_689690.3	Q8N9K5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF565	ENST00000304116.10 link	c.1064G>T	p.Arg355Ile	missense_variant	Exon 5 of 5	2	NM_152477.5	ENSP00000306869.5	Q8N9K5-2
ZNF565	ENST00000355114.9 link	c.1184G>T	p.Arg395Ile	missense_variant	Exon 5 of 5	2		ENSP00000347234.5	Q8N9K5-1
ZNF565	ENST00000392173.6 link	c.1064G>T	p.Arg355Ile	missense_variant	Exon 5 of 5	2		ENSP00000376013.1	Q8N9K5-2
ZNF565	ENST00000591473.1 link	c.*90G>T		downstream_gene_variant		1		ENSP00000465906.1	K7EL42

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251470

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73886

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1064G>T (p.R355I) alteration is located in exon 5 (coding exon 4) of the ZNF565 gene. This alteration results from a G to T substitution at nucleotide position 1064, causing the arginine (R) at amino acid position 355 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

Benign

0.31

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

.;.;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.59

T;.;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;L;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.1

D;D;D

REVEL

Benign

0.15

Sift

Benign

0.040

D;D;T

Sift4G

Uncertain

0.034

D;D;D

Vest4

0.48

MutPred

0.61

Loss of phosphorylation at S358 (P = 0.0504);Loss of phosphorylation at S358 (P = 0.0504);.;

MVP

0.53

MPC

1.6

ClinPred

0.97

GERP RS

4.7

Varity_R

0.54

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over