Genetic Variant ZNF449:p.Ala130Glu (chrX-135349144-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152695.6(ZNF449):c.389C>A(p.Ala130Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,188 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ZNF449
NM_152695.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.04

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10053602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF449	NM_152695.6 link	c.389C>A	p.Ala130Glu	missense_variant	Exon 3 of 5	ENST00000339249.5	NP_689908.3	Q6P9G9-1Q7Z3P1
ZNF449	XM_047441914.1 link	c.389C>A	p.Ala130Glu	missense_variant	Exon 3 of 5		XP_047297870.1
ZNF449	XM_017029351.2 link	c.44C>A	p.Ala15Glu	missense_variant	Exon 4 of 6		XP_016884840.1
ZNF449	XM_047441915.1 link	c.44C>A	p.Ala15Glu	missense_variant	Exon 4 of 6		XP_047297871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF449	ENST00000339249.5 link	c.389C>A	p.Ala130Glu	missense_variant	Exon 3 of 5	1	NM_152695.6	ENSP00000339585.4		Q6P9G9-1
ZNF449	ENST00000370761.7 link	c.*1531C>A		downstream_gene_variant		2		ENSP00000359797.3		Q6P9G9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183391

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67821

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389C>A (p.A130E) alteration is located in exon 3 (coding exon 2) of the ZNF449 gene. This alteration results from a C to A substitution at nucleotide position 389, causing the alanine (A) at amino acid position 130 to be replaced by a glutamic acid (E). 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

-0.51

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.034

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.027

M_CAP

Benign

0.044

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.97

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

REVEL

Benign

0.071

Sift

Uncertain

0.022

Sift4G

Benign

1.0

Polyphen

0.0030

Vest4

0.23

MutPred

0.26

Gain of disorder (P = 0.0561);

MVP

0.29

MPC

0.75

ClinPred

0.027

GERP RS

3.7

Varity_R

0.48

gMVP

0.47

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