Genetic Variant ZNF474:p.Ser274Cys (chr5-122152811-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_207317.3(ZNF474):c.821C>G(p.Ser274Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,954 control chromosomes in the GnomAD database, including 68,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.24 ( 5033 hom., cov: 32)

Exomes 𝑓: 0.29 ( 63620 hom. )

Consequence

ZNF474
NM_207317.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.00

Publications

25 publications found

Variant links:

Genes affected

ZNF474 (HGNC:23245): (zinc finger protein 474) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZNF474 links:

ZNF475 (HGNC:53564): (zinc finger protein 475)

ZNF475 links:

ENSG00000247311 (HGNC:):

ENSG00000247311 links:

ZNF474-AS1 (HGNC:41019): (ZNF474 antisense RNA 1)

ZNF474-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=0.0017801821).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF474	NM_207317.3 link	c.821C>G	p.Ser274Cys	missense_variant	Exon 2 of 2	ENST00000296600.5	NP_997200.1
ZNF474-AS1	XR_007058915.1 link	n.271+1813G>C		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF474	ENST00000296600.5 link	c.821C>G	p.Ser274Cys	missense_variant	Exon 2 of 2	1	NM_207317.3	ENSP00000296600.4

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

36749

AN:

151978

Hom.:

5039

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.397

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.332

Gnomad EAS

AF:

0.385

Gnomad SAS

AF:

0.339

Gnomad FIN

AF:

0.334

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.242

GnomAD2 exomes

AF:

0.287

AC:

72206

AN:

251252

AF XY:

0.296

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.226

Gnomad ASJ exome

AF:

0.342

Gnomad EAS exome

AF:

0.387

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.286

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.291

AC:

424986

AN:

1461858

Hom.:

63620

Cov.:

AF XY:

0.294

AC XY:

213972

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.106

AC:

3558

AN:

33480

American (AMR)

AF:

0.224

AC:

9998

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

8971

AN:

26136

East Asian (EAS)

AF:

0.374

AC:

14853

AN:

39696

South Asian (SAS)

AF:

0.351

AC:

30282

AN:

86256

European-Finnish (FIN)

AF:

0.330

AC:

17631

AN:

53416

Middle Eastern (MID)

AF:

0.363

AC:

2095

AN:

5768

European-Non Finnish (NFE)

AF:

0.288

AC:

320259

AN:

1111990

Other (OTH)

AF:

0.287

AC:

17339

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

20356

40712

61069

81425

101781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10672

21344

32016

42688

53360

<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:

0.241

AC:

36729

AN:

152096

Hom.:

5033

Cov.:

AF XY:

0.248

AC XY:

18469

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.114

AC:

4742

AN:

41518

American (AMR)

AF:

0.218

AC:

3332

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.332

AC:

1149

AN:

3466

East Asian (EAS)

AF:

0.385

AC:

1978

AN:

5142

South Asian (SAS)

AF:

0.339

AC:

1629

AN:

4810

European-Finnish (FIN)

AF:

0.334

AC:

3523

AN:

10562

Middle Eastern (MID)

AF:

0.344

AC:

101

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19410

AN:

67994

Other (OTH)

AF:

0.239

AC:

504

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1391

2782

4173

5564

6955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.287

Hom.:

4863

Bravo

AF:

0.227

TwinsUK

AF:

0.285

AC:

1056

ALSPAC

AF:

0.286

AC:

1104

ESP6500AA

AF:

0.116

AC:

512

ESP6500EA

AF:

0.282

AC:

2424

ExAC

AF:

0.286

AC:

34695

Asia WGS

AF:

0.293

AC:

1020

AN:

3478

EpiCase

AF:

0.290

EpiControl

AF:

0.285

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.012

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

PhyloP100

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Uncertain

0.025

Sift4G

Uncertain

0.021

Polyphen

0.98

Vest4

0.036

MPC

0.012

ClinPred

0.016

GERP RS

2.5

Varity_R

0.093

gMVP

0.090

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