Genetic Variant ZNF532:p.Leu253Val (chr18-58919044-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001375912.1(ZNF532):c.757C>G(p.Leu253Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,613,924 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 16 hom. )

Consequence

ZNF532
NM_001375912.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.733

Publications

3 publications found

Variant links:

Genes affected

ZNF532 (HGNC:30940): (zinc finger protein 532) Predicted to enable DNA binding activity and metal ion binding activity. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF532 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=0.0032782257).

BP6

Variant 18-58919044-C-G is Benign according to our data. Variant chr18-58919044-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 773073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0011 (1613/1461656) while in subpopulation MID AF = 0.0303 (175/5768). AF 95% confidence interval is 0.0267. There are 16 homozygotes in GnomAdExome4. There are 822 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 176 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375912.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF532	NM_001375912.1	MANE Select	c.757C>G	p.Leu253Val	missense	Exon 3 of 10	NP_001362841.1	Q9HCE3
ZNF532	NM_001318726.2		c.757C>G	p.Leu253Val	missense	Exon 3 of 10	NP_001305655.1	Q9HCE3
ZNF532	NM_001318727.2		c.757C>G	p.Leu253Val	missense	Exon 3 of 10	NP_001305656.1	Q9HCE3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF532	ENST00000591808.6	TSL:1 MANE Select	c.757C>G	p.Leu253Val	missense	Exon 3 of 10	ENSP00000468238.1	Q9HCE3
ZNF532	ENST00000336078.8	TSL:1	c.757C>G	p.Leu253Val	missense	Exon 4 of 11	ENSP00000338217.4	Q9HCE3
ZNF532	ENST00000591083.5	TSL:1	c.757C>G	p.Leu253Val	missense	Exon 3 of 10	ENSP00000468532.1	Q9HCE3

Frequencies

GnomAD3 genomes

AF:

0.00116

AC:

176

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00181

AC:

454

AN:

250190

AF XY:

0.00194

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00110

AC:

1613

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

822

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

564

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53184

Middle Eastern (MID)

AF:

0.0303

AC:

175

AN:

5768

European-Non Finnish (NFE)

AF:

0.000523

AC:

582

AN:

1112010

Other (OTH)

AF:

0.00298

AC:

180

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.00116

AC:

176

AN:

152268

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41556

American (AMR)

AF:

0.00248

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000779

AC:

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00478

Hom.:

Bravo

AF:

0.00155

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00163

AC:

198

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.4

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.0085

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.67

M_CAP

Benign

0.0071

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

PhyloP100

0.73

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.060

REVEL

Benign

0.044

Sift

Benign

0.91

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.034

MVP

0.068

MPC

0.55

ClinPred

0.0055

GERP RS

1.0

Varity_R

0.089

gMVP

0.024

Mutation Taster

=100/0

polymorphism

(source)

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

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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