Genetic Variant ZNF417:p.Val453Ile (chr19-57908921-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152475.3(ZNF417):c.1357G>A(p.Val453Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,612,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

ZNF417
NM_152475.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -8.74

Variant links:

Genes affected

ZNF417 (HGNC:20646): (zinc finger protein 417) 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. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF417 links:

ENSG00000269476 (HGNC:):

ENSG00000269476 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.026513815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF417	NM_152475.3 link	c.1357G>A	p.Val453Ile	missense_variant	Exon 3 of 3	ENST00000312026.6	NP_689688.2	Q8TAU3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF417	ENST00000312026.6 link	c.1357G>A	p.Val453Ile	missense_variant	Exon 3 of 3	1	NM_152475.3	ENSP00000311319.4	Q8TAU3-1
ZNF417	ENST00000595559.1 link	c.1354G>A	p.Val452Ile	missense_variant	Exon 3 of 3	1		ENSP00000472272.1	M0R230
ENSG00000269476	ENST00000602124.1 link	n.34+3139G>A		intron_variant	Intron 3 of 5	3		ENSP00000470782.1	M0QZU9
ZNF417	ENST00000594396.1 link	c.106+3139G>A		intron_variant	Intron 1 of 2	3		ENSP00000472352.1	M0R267

Frequencies

GnomAD3 genomes

AF:

0.000172

AC:

AN:

151082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000973

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00139

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251304

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000428

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000172

AC:

AN:

151200

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

AN XY:

73888

show subpopulations

Gnomad4 AFR

AF:

0.0000970

Gnomad4 AMR

AF:

0.00138

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000321

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1357G>A (p.V453I) alteration is located in exon 3 (coding exon 3) of the ZNF417 gene. This alteration results from a G to A substitution at nucleotide position 1357, causing the valine (V) at amino acid position 453 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.13

DANN

Benign

0.84

DEOGEN2

Benign

0.0019

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0059

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.0012

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.095

N;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.35

N;.

REVEL

Benign

0.0020

Sift

Benign

0.40

T;.

Sift4G

Benign

0.36

T;T

Polyphen

0.012

B;.

Vest4

0.032

MVP

0.25

ClinPred

0.035

GERP RS

-3.0

Varity_R

0.020

gMVP

0.011

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