Genetic Variant ZNF449:p.Val479Ile (chrX-135360954-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152695.6(ZNF449):c.1435G>A(p.Val479Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,209,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000048 ( 0 hom. 26 hem. )

Consequence

ZNF449
NM_152695.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Variant links:

Genes affected

ZNF449 (HGNC:21039): (zinc finger protein 449) This gene encodes a nuclear protein that likely functions as a transcription factor. The protein includes an N-terminal SCAN domain, and seven C2H2-type zinc finger motifs. [provided by RefSeq, May 2010]

ZNF449 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024029553).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF449	NM_152695.6 link	c.1435G>A	p.Val479Ile	missense_variant	Exon 5 of 5	ENST00000339249.5	NP_689908.3	Q6P9G9-1Q7Z3P1
ZNF449	XM_047441914.1 link	c.1435G>A	p.Val479Ile	missense_variant	Exon 5 of 5		XP_047297870.1
ZNF449	XM_017029351.2 link	c.1090G>A	p.Val364Ile	missense_variant	Exon 6 of 6		XP_016884840.1
ZNF449	XM_047441915.1 link	c.1090G>A	p.Val364Ile	missense_variant	Exon 6 of 6		XP_047297871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF449	ENST00000339249.5 link	c.1435G>A	p.Val479Ile	missense_variant	Exon 5 of 5	1	NM_152695.6	ENSP00000339585.4		Q6P9G9-1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111466

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

33722

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000740

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

182989

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

67539

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000474

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000483

AC:

AN:

1097897

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

363333

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000993

Gnomad4 SAS exome

AF:

0.000647

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000166

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000359

AC:

AN:

111466

Hom.:

Cov.:

AF XY:

0.0000890

AC XY:

AN XY:

33722

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000948

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000740

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000189

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 28, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1435G>A (p.V479I) alteration is located in exon 5 (coding exon 4) of the ZNF449 gene. This alteration results from a G to A substitution at nucleotide position 1435, causing the valine (V) at amino acid position 479 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

0.12

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Benign

0.27

DEOGEN2

Benign

0.024

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.70

M_CAP

Benign

0.0026

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.26

PrimateAI

Benign

0.48

PROVEAN

Benign

0.13

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Benign

0.76

Polyphen

0.27

Vest4

0.033

MutPred

0.51

Loss of MoRF binding (P = 0.1064);

MVP

0.35

MPC

0.58

ClinPred

0.059

GERP RS

3.7

Varity_R

0.064

gMVP

0.24

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