rs138082392

Variant names:

• chr19-42225228-C-T
• rs138082392
• NM_133444.3:c.825C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_133444.3(ZNF526):​c.825C>T​(p.Cys275Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000278 in 1,613,994 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: ZNF526 NM_133444.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.978
• Publications: 1 publications found

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]

ZNF526 Gene-Disease associations (from GenCC):

• Dentici-Novelli neurodevelopmental syndrome

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ENSG00000288671 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-42225228-C-T is Benign according to our data. Variant chr19-42225228-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437386.
• BP7: Synonymous conserved (PhyloP=0.978 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133444.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF526	NM_133444.3	MANE Select	c.825C>T	p.Cys275Cys	synonymous	Exon 3 of 3	NP_597701.1	H9ZYJ3
	ZNF526	NM_001314033.3		c.825C>T	p.Cys275Cys	synonymous	Exon 3 of 3	NP_001300962.1	H9ZYJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF526	ENST00000301215.8	TSL:1 MANE Select	c.825C>T	p.Cys275Cys	synonymous	Exon 3 of 3	ENSP00000301215.2	Q8TF50
	ENSG00000288671	ENST00000678490.1		c.91+6829G>A		intron	N/A	ENSP00000502878.1	A0A7I2V2F5
	ZNF526	ENST00000710326.1		c.825C>T	p.Cys275Cys	synonymous	Exon 3 of 3	ENSP00000518206.1	Q8TF50

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000240 AC: 60 AN: 250452 AF XY: 0.000214

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000285 AC: 416 AN: 1461774 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 195 AN XY: 727174

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000367 AC: 408 AN: 1111948

Other (OTH) AF: 0.000116 AC: 7 AN: 60382

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74360

African (AFR) AF: 0.000121 AC: 5 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000215

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	ZNF526-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.3
DANN	Benign	0.83
PhyloP100		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138082392; hg19: chr19-42729380; COSMIC: COSV55899222; COSMIC: COSV55899222;