chr19-42224882-A-C

Variant names:

• chr19-42224882-A-C
• rs730882205
• NM_133444.3:c.479A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_Moderate BP4

The NM_133444.3(ZNF526):​c.479A>C​(p.Lys160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,848 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 Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF526 NM_133444.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 2.20
• Publications: 2 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000288671 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 19-42224882-A-C is Pathogenic according to our data. Variant chr19-42224882-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183288.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38166898). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF526	NM_133444.3	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3	ENST00000301215.8	NP_597701.1
ZNF526	NM_001314033.3	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3		NP_001300962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF526	ENST00000301215.8	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3	1	NM_133444.3	ENSP00000301215.2
ENSG00000288671	ENST00000678490.1	c.91+7175T>G		intron_variant	Intron 1 of 1			ENSP00000502878.1
ZNF526	ENST00000710326.1	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3			ENSP00000518206.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000542 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Dentici-Novelli neurodevelopmental syndrome Pathogenic:1

Jan 13, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Pulmonic stenosis;C3714756:Intellectual disability;CN228297:Noonan-like facies Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.030	D
Polyphen		0.021	B
Vest4		0.75
MutPred		0.44		Loss of ubiquitination at K160 (P = 0.0116);
MVP		0.25
MPC		0.71
ClinPred		0.42	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.29
Mutation Taster		=34/66	disease causing (ClinVar)

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: rs730882205; hg19: chr19-42729034;