Genetic Variant ZNF256:p.Val624Ile (chr19-57940938-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005773.3(ZNF256):c.1870G>A(p.Val624Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,302 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: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ZNF256
NM_005773.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.449

Variant links:

Genes affected

ZNF256 (HGNC:13049): (zinc finger protein 256) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription, DNA-templated. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF256 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049611986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF256	NM_005773.3 link	c.1870G>A	p.Val624Ile	missense_variant	Exon 3 of 3	ENST00000282308.4	NP_005764.2	Q9Y2P7-1
ZNF256	NM_001375403.1 link	c.1411G>A	p.Val471Ile	missense_variant	Exon 2 of 2		NP_001362332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF256	ENST00000282308.4 link	c.1870G>A	p.Val624Ile	missense_variant	Exon 3 of 3	1	NM_005773.3	ENSP00000282308.2		Q9Y2P7-1
ZNF256	ENST00000598928 link	c.*1572G>A		3_prime_UTR_variant	Exon 2 of 2	1		ENSP00000472858.1		M0R2X0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

251006

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461146

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726774

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1870G>A (p.V624I) alteration is located in exon 3 (coding exon 3) of the ZNF256 gene. This alteration results from a G to A substitution at nucleotide position 1870, causing the valine (V) at amino acid position 624 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

0.073

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.0059

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.14

M_CAP

Benign

0.0019

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.63

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.43

REVEL

Benign

0.065

Sift

Benign

0.43

Sift4G

Benign

0.31

Polyphen

0.052

Vest4

0.067

MutPred

0.47

Gain of methylation at K626 (P = 0.0774);

MVP

0.061

MPC

0.049

ClinPred

0.014

GERP RS

-1.8

Varity_R

0.0096

gMVP

0.024

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