chr19-42224684-T-C

Position:

• chr19-42224684-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_133444.3(ZNF526):​c.281T>C​(p.Val94Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,614,138 control chromosomes in the GnomAD database, including 9,141 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.079 (663 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8478 hom.)
• Consequence: ZNF526 NM_133444.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.367

Genes affected

ZNF526 (HGNC:29415): (zinc finger protein 526) 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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.889007E-4).
• BP6: Variant 19-42224684-T-C is Benign according to our data. Variant chr19-42224684-T-C is described in ClinVar as [Benign]. Clinvar id is 130837.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-42224684-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF526	NM_133444.3	c.281T>C	p.Val94Ala	missense_variant	3/3	ENST00000301215.8
ZNF526	NM_001314033.3	c.281T>C	p.Val94Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF526	ENST00000301215.8	c.281T>C	p.Val94Ala	missense_variant	3/3	1	NM_133444.3	P1
ZNF526	ENST00000710326.1	c.281T>C	p.Val94Ala	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes AF: 0.0791 AC: 12042 AN: 152156 Hom.: 665 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.0903

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0506

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0966

GnomAD3 exomes AF: 0.109 AC: 27336 AN: 251264 Hom.: 1738 AF XY: 0.114 AC XY: 15414 AN XY: 135792

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.0947

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.0527

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.103 AC: 150203 AN: 1461864 Hom.: 8478 Cov.: 32 AF XY: 0.106 AC XY: 76757 AN XY: 727234

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.0737

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0790 AC: 12029 AN: 152274 Hom.: 663 Cov.: 32 AF XY: 0.0791 AC XY: 5887 AN XY: 74458

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.0999

Gnomad4 EAS AF: 0.0897

Gnomad4 SAS AF: 0.178

Gnomad4 FIN AF: 0.0506

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0980 Hom.: 1251

Bravo AF: 0.0813

TwinsUK AF: 0.0979 AC: 363

ALSPAC AF: 0.0950 AC: 366

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.101 AC: 865

ExAC AF: 0.109 AC: 13276

Asia WGS AF: 0.133 AC: 462 AN: 3478

EpiCase AF: 0.109

EpiControl AF: 0.108

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

ZNF526-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.040
DANN	Benign	0.30
DEOGEN2	Benign	0.0079	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.00099	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.037
Sift	Benign	0.76	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.37
ClinPred		0.00087	T
GERP RS		1.7
Varity_R		0.020
gMVP		0.11

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

Other links and lift over

dbSNP: rs3810151; hg19: chr19-42728836; COSMIC: COSV56628837; COSMIC: COSV56628837;