Genetic Variant ZNF474:p.Arg173His (chr5-122152508-G-A) – 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.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0607 in 1,613,948 control chromosomes in the GnomAD database, including 5,348 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R173C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1880 hom., cov: 32)

Exomes 𝑓: 0.055 ( 3468 hom. )

Consequence

ZNF474
NM_207317.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.861

Publications

11 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=0.0050495863).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF474	NM_207317.3 link	c.518G>A	p.Arg173His	missense_variant	Exon 2 of 2	ENST00000296600.5	NP_997200.1	Q6S9Z5
ZNF474-AS1	XR_007058915.1 link	n.272-1905C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF474	ENST00000296600.5 link	c.518G>A	p.Arg173His	missense_variant	Exon 2 of 2	1	NM_207317.3	ENSP00000296600.4		Q6S9Z5

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17839

AN:

151978

Hom.:

1875

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0592

Gnomad ASJ

AF:

0.0303

Gnomad EAS

AF:

0.0992

Gnomad SAS

AF:

0.0637

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0443

Gnomad OTH

AF:

0.0989

GnomAD2 exomes

AF:

0.0708

AC:

17735

AN:

250524

AF XY:

0.0668

show subpopulations

Gnomad AFR exome

AF:

0.294

Gnomad AMR exome

AF:

0.0347

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.0433

Gnomad OTH exome

AF:

0.0567

GnomAD4 exome

AF:

0.0548

AC:

80077

AN:

1461852

Hom.:

3468

Cov.:

AF XY:

0.0544

AC XY:

39562

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.296

AC:

9926

AN:

33480

American (AMR)

AF:

0.0376

AC:

1682

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0301

AC:

787

AN:

26134

East Asian (EAS)

AF:

0.0836

AC:

3319

AN:

39698

South Asian (SAS)

AF:

0.0618

AC:

5332

AN:

86256

European-Finnish (FIN)

AF:

0.0987

AC:

5273

AN:

53398

Middle Eastern (MID)

AF:

0.0546

AC:

315

AN:

5768

European-Non Finnish (NFE)

AF:

0.0445

AC:

49479

AN:

1112004

Other (OTH)

AF:

0.0656

AC:

3964

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

5058

10116

15174

20232

25290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2046

4092

6138

8184

10230

<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:

0.118

AC:

17874

AN:

152096

Hom.:

1880

Cov.:

AF XY:

0.119

AC XY:

8858

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.281

AC:

11640

AN:

41458

American (AMR)

AF:

0.0591

AC:

903

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0303

AC:

105

AN:

3466

East Asian (EAS)

AF:

0.0992

AC:

512

AN:

5160

South Asian (SAS)

AF:

0.0638

AC:

307

AN:

4814

European-Finnish (FIN)

AF:

0.107

AC:

1134

AN:

10584

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0443

AC:

3016

AN:

68014

Other (OTH)

AF:

0.100

AC:

212

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

708

1416

2125

2833

3541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<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:

0.0607

Hom.:

2195

Bravo

AF:

0.122

TwinsUK

AF:

0.0399

AC:

148

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.281

AC:

1239

ESP6500EA

AF:

0.0435

AC:

374

ExAC

AF:

0.0747

AC:

9067

Asia WGS

AF:

0.0870

AC:

303

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.22

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

0.86

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.33

Sift

Benign

0.036

Sift4G

Uncertain

0.038

Polyphen

0.15

Vest4

0.11

MPC

0.0036

ClinPred

0.093

GERP RS

0.80

Varity_R

0.27

gMVP

0.20

Mutation Taster

=99/1

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