Genetic Variant ZNF536:p.Ala1048Val (chr19-30548762-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014717.3(ZNF536):c.3143C>T(p.Ala1048Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,832 control chromosomes in the GnomAD database, including 1,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 135 hom., cov: 33)

Exomes 𝑓: 0.036 ( 1373 hom. )

Consequence

ZNF536
NM_014717.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0720

Publications

14 publications found

Variant links:

Genes affected

ZNF536 (HGNC:29025): (zinc finger protein 536) The protein encoded by this gene is a highly conserved zinc finger protein. The encoded protein is most abundant in brain, where it negatively regulates neuronal differentiation. [provided by RefSeq, Sep 2015]

ZNF536 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017009676).

BP6

Variant 19-30548762-C-T is Benign according to our data. Variant chr19-30548762-C-T is described in ClinVar as [Benign]. Clinvar id is 403626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF536	NM_014717.3 link	c.3143C>T	p.Ala1048Val	missense_variant	Exon 4 of 5	ENST00000355537.4	NP_055532.1	O15090

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF536	ENST00000355537.4 link	c.3143C>T	p.Ala1048Val	missense_variant	Exon 4 of 5	1	NM_014717.3	ENSP00000347730.1		O15090

Frequencies

GnomAD3 genomes

AF:

0.0330

AC:

5024

AN:

152096

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0314

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0228

Gnomad ASJ

AF:

0.0187

Gnomad EAS

AF:

0.00368

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0364

AC:

9128

AN:

251030

AF XY:

0.0401

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0185

Gnomad EAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0321

Gnomad OTH exome

AF:

0.0344

GnomAD4 exome

AF:

0.0361

AC:

52831

AN:

1461618

Hom.:

1373

Cov.:

AF XY:

0.0382

AC XY:

27804

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0319

AC:

1067

AN:

33480

American (AMR)

AF:

0.0179

AC:

802

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

492

AN:

26136

East Asian (EAS)

AF:

0.00186

AC:

AN:

39700

South Asian (SAS)

AF:

0.110

AC:

9507

AN:

86258

European-Finnish (FIN)

AF:

0.0202

AC:

1072

AN:

53152

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0339

AC:

37678

AN:

1112004

Other (OTH)

AF:

0.0340

AC:

2054

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3366

6733

10099

13466

16832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0330

AC:

5024

AN:

152214

Hom.:

135

Cov.:

AF XY:

0.0338

AC XY:

2512

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0314

AC:

1303

AN:

41552

American (AMR)

AF:

0.0227

AC:

347

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0187

AC:

AN:

3472

East Asian (EAS)

AF:

0.00349

AC:

AN:

5152

South Asian (SAS)

AF:

0.121

AC:

585

AN:

4822

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0352

AC:

2395

AN:

67992

Other (OTH)

AF:

0.0303

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

248

496

745

993

1241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0313

Hom.:

274

Bravo

AF:

0.0297

TwinsUK

AF:

0.0324

AC:

120

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.0365

AC:

161

ESP6500EA

AF:

0.0335

AC:

288

ExAC

AF:

0.0383

AC:

4653

Asia WGS

AF:

0.0600

AC:

208

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0317

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.85

CADD

Benign

8.7

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.032

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.20

PhyloP100

0.072

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.89

REVEL

Benign

0.025

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.0020

Vest4

0.022

MPC

0.12

ClinPred

0.0026

GERP RS

0.61

Varity_R

0.025

gMVP

0.27

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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19-30548762-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over