Genetic Variant ZNF45:p.Arg504Lys (chr19-43913925-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003425.4(ZNF45):c.1511G>A(p.Arg504Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,612,264 control chromosomes in the GnomAD database, including 210,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.49 ( 18785 hom., cov: 30)

Exomes 𝑓: 0.51 ( 191371 hom. )

Consequence

ZNF45
NM_003425.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45

Publications

46 publications found

Variant links:

Genes affected

ZNF45 (HGNC:13111): (zinc finger protein 45) 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. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF45 links:

ZNF45-AS1 (HGNC:55308): (ZNF45 antisense RNA 1)

ZNF45-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=7.285123E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF45	NM_003425.4 link	c.1511G>A	p.Arg504Lys	missense_variant	Exon 10 of 10	ENST00000269973.10	NP_003416.1	Q02386

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF45	ENST00000269973.10 link	c.1511G>A	p.Arg504Lys	missense_variant	Exon 10 of 10	2	NM_003425.4	ENSP00000269973.4		Q02386

Frequencies

GnomAD3 genomes

AF:

0.488

AC:

73590

AN:

150698

Hom.:

18761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.357

Gnomad AMI

AF:

0.604

Gnomad AMR

AF:

0.629

Gnomad ASJ

AF:

0.489

Gnomad EAS

AF:

0.814

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.521

Gnomad MID

AF:

0.450

Gnomad NFE

AF:

0.509

Gnomad OTH

AF:

0.485

GnomAD2 exomes

AF:

0.538

AC:

134856

AN:

250878

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.341

Gnomad AMR exome

AF:

0.708

Gnomad ASJ exome

AF:

0.495

Gnomad EAS exome

AF:

0.818

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.510

Gnomad OTH exome

AF:

0.526

GnomAD4 exome

AF:

0.506

AC:

739506

AN:

1461446

Hom.:

191371

Cov.:

AF XY:

0.502

AC XY:

364869

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.346

AC:

11579

AN:

33468

American (AMR)

AF:

0.696

AC:

31128

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

12791

AN:

26120

East Asian (EAS)

AF:

0.833

AC:

33077

AN:

39686

South Asian (SAS)

AF:

0.402

AC:

34639

AN:

86234

European-Finnish (FIN)

AF:

0.530

AC:

28286

AN:

53406

Middle Eastern (MID)

AF:

0.446

AC:

2574

AN:

5768

European-Non Finnish (NFE)

AF:

0.499

AC:

554783

AN:

1111680

Other (OTH)

AF:

0.508

AC:

30649

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

22291

44583

66874

89166

111457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16176

32352

48528

64704

80880

<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:

0.488

AC:

73650

AN:

150818

Hom.:

18785

Cov.:

AF XY:

0.494

AC XY:

36384

AN XY:

73656

show subpopulations

African (AFR)

AF:

0.358

AC:

14640

AN:

40940

American (AMR)

AF:

0.629

AC:

9581

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.489

AC:

1684

AN:

3444

East Asian (EAS)

AF:

0.814

AC:

4165

AN:

5114

South Asian (SAS)

AF:

0.426

AC:

2017

AN:

4734

European-Finnish (FIN)

AF:

0.521

AC:

5438

AN:

10440

Middle Eastern (MID)

AF:

0.446

AC:

125

AN:

280

European-Non Finnish (NFE)

AF:

0.509

AC:

34429

AN:

67636

Other (OTH)

AF:

0.488

AC:

1025

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1830

3661

5491

7322

9152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

648

1296

1944

2592

3240

<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:

0.505

Hom.:

66356

Bravo

AF:

0.491

TwinsUK

AF:

0.500

AC:

1855

ALSPAC

AF:

0.500

AC:

1926

ESP6500AA

AF:

0.359

AC:

1581

ESP6500EA

AF:

0.506

AC:

4351

ExAC

AF:

0.527

AC:

64003

Asia WGS

AF:

0.593

AC:

2060

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.010

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.00047

LIST_S2

Benign

0.0087

.;T;.

MetaRNN

Benign

7.3e-7

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.21

N;N;N

PhyloP100

1.4

PrimateAI

Benign

0.48

PROVEAN

Benign

1.1

N;.;.

REVEL

Benign

0.034

Sift

Benign

0.32

T;.;.

Sift4G

Benign

0.56

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.026

MPC

0.18

ClinPred

0.0069

GERP RS

2.6

Varity_R

0.089

gMVP

0.023

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over