dbSNP rs2560306: ZNF474:p.Arg173His (chr5-122152508-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. 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

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:

ENSG00000250803 (HGNC:53564): (zinc finger protein 475)

ENSG00000250803 links:

ENSG00000247311 (HGNC:):

ENSG00000247311 links:

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

ZNF474-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.0708

AC:

17735

AN:

250524

Hom.:

1171

AF XY:

0.0668

AC XY:

9044

AN XY:

135376

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 SAS exome

AF:

0.0616

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

Gnomad4 AFR exome

AF:

0.296

Gnomad4 AMR exome

AF:

0.0376

Gnomad4 ASJ exome

AF:

0.0301

Gnomad4 EAS exome

AF:

0.0836

Gnomad4 SAS exome

AF:

0.0618

Gnomad4 FIN exome

AF:

0.0987

Gnomad4 NFE exome

AF:

0.0445

Gnomad4 OTH exome

AF:

0.0656

GnomAD4 genome

AF:

0.118

AC:

17874

AN:

152096

Hom.:

1880

Cov.:

AF XY:

0.119

AC XY:

8858

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.0591

Gnomad4 ASJ

AF:

0.0303

Gnomad4 EAS

AF:

0.0992

Gnomad4 SAS

AF:

0.0638

Gnomad4 FIN

AF:

0.107

Gnomad4 NFE

AF:

0.0443

Gnomad4 OTH

AF:

0.100

Alfa

AF:

0.0574

Hom.:

1002

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over