Variant 19-57779380-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_017652.4(ZNF586):c.793G>A(p.Val265Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,460,474 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000095 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

ZNF586
NM_017652.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.12

Variant links:

Genes affected

ZNF586 (HGNC:25949): (zinc finger protein 586) 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]

ZNF586 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=0.055212736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF586	NM_017652.4 linkuse as main transcript	c.793G>A	p.Val265Ile	missense_variant	3/3	ENST00000396154.7	NP_060122.2	Q9NXT0-1
ZNF586	NM_001204814.2 linkuse as main transcript	c.664G>A	p.Val222Ile	missense_variant	4/4		NP_001191743.1	Q9NXT0-3
ZNF586	NM_001077426.3 linkuse as main transcript	c.*33G>A		3_prime_UTR_variant	2/2		NP_001070894.1	Q9NXT0-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF586	ENST00000396154.7 linkuse as main transcript	c.793G>A	p.Val265Ile	missense_variant	3/3	1	NM_017652.4	ENSP00000379458.1		Q9NXT0-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

136410

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000232

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000218

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250084

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1460474

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

726614

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000297

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000952

AC:

AN:

136522

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

66636

show subpopulations

Gnomad4 AFR

AF:

0.000167

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000233

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000218

Gnomad4 NFE

AF:

0.0000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000270

Hom.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 20, 2023

The c.793G>A (p.V265I) alteration is located in exon 3 (coding exon 3) of the ZNF586 gene. This alteration results from a G to A substitution at nucleotide position 793, causing the valine (V) at amino acid position 265 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

0.082

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.8

DANN

Uncertain

0.98

DEOGEN2

Benign

0.011

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0088

LIST_S2

Benign

0.11

T;T

M_CAP

Benign

0.00054

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.64

.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.22

N;N

REVEL

Benign

0.083

Sift

Benign

0.051

T;T

Sift4G

Uncertain

0.044

D;D

Polyphen

0.98

.;D

Vest4

0.048

MVP

0.072

MPC

0.063

ClinPred

0.073

GERP RS

-1.2

Varity_R

0.018

gMVP

0.040

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