Genetic Variant ZNF474:p.Arg90His (chr5-122152259-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_207317.3(ZNF474):c.269G>A(p.Arg90His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,178 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0099 ( 31 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 24 hom. )

Consequence

ZNF474
NM_207317.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.85

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009177774).

BP6

Variant 5-122152259-G-A is Benign according to our data. Variant chr5-122152259-G-A is described in ClinVar as [Benign]. Clinvar id is 784058.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00989 (1506/152300) while in subpopulation AFR AF= 0.0335 (1393/41566). AF 95% confidence interval is 0.032. There are 31 homozygotes in gnomad4. There are 726 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF474	NM_207317.3 link	c.269G>A	p.Arg90His	missense_variant	Exon 2 of 2	ENST00000296600.5	NP_997200.1	Q6S9Z5
ZNF474-AS1	XR_007058915.1 link	n.272-1656C>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.269G>A	p.Arg90His	missense_variant	Exon 2 of 2	1	NM_207317.3	ENSP00000296600.4		Q6S9Z5

Frequencies

GnomAD3 genomes

AF:

0.00987

AC:

1502

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0335

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00279

AC:

699

AN:

250730

Hom.:

AF XY:

0.00205

AC XY:

278

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00117

AC:

1709

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

771

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0335

Gnomad4 AMR exome

AF:

0.00360

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000201

Gnomad4 OTH exome

AF:

0.00260

GnomAD4 genome

AF:

0.00989

AC:

1506

AN:

152300

Hom.:

Cov.:

AF XY:

0.00975

AC XY:

726

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0335

Gnomad4 AMR

AF:

0.00464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00614

Alfa

AF:

0.00161

Hom.:

Bravo

AF:

0.0118

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0331

AC:

146

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.00328

AC:

398

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.019

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0092

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.2

REVEL

Benign

0.12

Sift

Benign

0.061

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.37

MVP

0.56

MPC

0.014

ClinPred

0.016

GERP RS

4.7

Varity_R

0.12

gMVP

0.084

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over