19-42224904-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_133444.3(ZNF526):c.501G>A(p.Thr167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,008 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (6 hom.)
• Consequence: ZNF526 NM_133444.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.28

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-42224904-G-A is Benign according to our data. Variant chr19-42224904-G-A is described in ClinVar as [Benign]. Clinvar id is 130832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00616 (937/152144) while in subpopulation AFR AF= 0.0214 (886/41494). AF 95% confidence interval is 0.0202. There are 13 homozygotes in gnomad4. There are 465 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF526	NM_133444.3	c.501G>A	p.Thr167=	synonymous_variant	3/3	ENST00000301215.8
ZNF526	NM_001314033.3	c.501G>A	p.Thr167=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF526	ENST00000301215.8	c.501G>A	p.Thr167=	synonymous_variant	3/3	1	NM_133444.3	P1
ZNF526	ENST00000710326.1	c.501G>A	p.Thr167=	synonymous_variant	3/3			P1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152026 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00172 AC: 432 AN: 251262 Hom.: 2 AF XY: 0.00124 AC XY: 169 AN XY: 135820

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000657 AC: 960 AN: 1461864 Hom.: 6 Cov.: 32 AF XY: 0.000573 AC XY: 417 AN XY: 727236

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00616 AC: 937 AN: 152144 Hom.: 13 Cov.: 32 AF XY: 0.00625 AC XY: 465 AN XY: 74396

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00266 Hom.: 2

Bravo AF: 0.00716

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.73
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs57984044; hg19: chr19-42729056; COSMIC: COSV56630937; COSMIC: COSV56630937;