Genetic Variant ZNF568:p.Ala427Val (chr19-36996971-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001204838.2(ZNF568):c.1280C>T(p.Ala427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,541,896 control chromosomes in the GnomAD database, including 359 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.016 ( 24 hom., cov: 31)

Exomes 𝑓: 0.019 ( 335 hom. )

Consequence

ZNF568
NM_001204838.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00

Publications

20 publications found

Variant links:

Genes affected

ZNF568 (HGNC:25392): (zinc finger protein 568) 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 embryonic placenta morphogenesis and negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF568 links:

ENSG00000291239 (HGNC:):

ENSG00000291239 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006697446).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0158 (2397/151334) while in subpopulation SAS AF = 0.0357 (171/4784). AF 95% confidence interval is 0.0314. There are 24 homozygotes in GnomAd4. There are 1198 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204838.2. 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
	ZNF568	NM_001204838.2		c.1280C>T	p.Ala427Val	missense	Exon 10 of 10	NP_001191767.1	C9JLX5
	ZNF568	NM_001204839.2		c.1088C>T	p.Ala363Val	missense	Exon 9 of 9	NP_001191768.1	Q3ZCX4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF568	ENST00000444991.6	TSL:1	c.1280C>T	p.Ala427Val	missense	Exon 10 of 10	ENSP00000389794.2	C9JLX5
ENSG00000291239	ENST00000706165.1		c.1280C>T	p.Ala427Val	missense	Exon 12 of 12	ENSP00000516244.1	C9JLX5
ZNF568	ENST00000591887.1	TSL:1	n.1449C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2400

AN:

151214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0184

Gnomad ASJ

AF:

0.0300

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.0357

Gnomad FIN

AF:

0.00487

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0171

Gnomad OTH

AF:

0.0250

GnomAD2 exomes

AF:

0.0198

AC:

3013

AN:

151806

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.0160

Gnomad ASJ exome

AF:

0.0367

Gnomad EAS exome

AF:

0.000356

Gnomad FIN exome

AF:

0.00524

Gnomad NFE exome

AF:

0.0176

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0191

AC:

26500

AN:

1390562

Hom.:

335

Cov.:

AF XY:

0.0199

AC XY:

13669

AN XY:

686746

show subpopulations

African (AFR)

AF:

0.0137

AC:

434

AN:

31714

American (AMR)

AF:

0.0162

AC:

584

AN:

35992

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

879

AN:

25210

East Asian (EAS)

AF:

0.000195

AC:

AN:

35930

South Asian (SAS)

AF:

0.0401

AC:

3192

AN:

79636

European-Finnish (FIN)

AF:

0.00694

AC:

250

AN:

36024

Middle Eastern (MID)

AF:

0.0424

AC:

242

AN:

5704

European-Non Finnish (NFE)

AF:

0.0182

AC:

19688

AN:

1082124

Other (OTH)

AF:

0.0210

AC:

1224

AN:

58228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1566

3132

4699

6265

7831

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

760

1520

2280

3040

3800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0158

AC:

2397

AN:

151334

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1198

AN XY:

73916

show subpopulations

African (AFR)

AF:

0.0138

AC:

567

AN:

41214

American (AMR)

AF:

0.0183

AC:

278

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

104

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5116

South Asian (SAS)

AF:

0.0357

AC:

171

AN:

4784

European-Finnish (FIN)

AF:

0.00487

AC:

AN:

10468

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1163

AN:

67758

Other (OTH)

AF:

0.0242

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00251

Hom.:

18350

TwinsUK

AF:

0.0216

AC:

ALSPAC

AF:

0.0179

AC:

ExAC

AF:

0.0122

AC:

1229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.1

PhyloP100

2.0

PROVEAN

Benign

-0.63

REVEL

Benign

0.069

Sift

Benign

0.17

Sift4G

Benign

0.15

Vest4

0.083

ClinPred

0.0069

GERP RS

3.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over