Variant X-135349264-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000339249.5(ZNF449):c.509C>T(p.Pro170Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,209,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 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 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 17 hem. )

Consequence

ZNF449
ENST00000339249.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.03

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08127743).

BS2

High Hemizygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZNF449	NM_152695.6 linkuse as main transcript	c.509C>T	p.Pro170Leu	missense_variant	3/5	ENST00000339249.5	NP_689908.3
ZNF449	XM_047441914.1 linkuse as main transcript	c.509C>T	p.Pro170Leu	missense_variant	3/5		XP_047297870.1
ZNF449	XM_017029351.2 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	4/6		XP_016884840.1
ZNF449	XM_047441915.1 linkuse as main transcript	c.164C>T	p.Pro55Leu	missense_variant	4/6		XP_047297871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF449	ENST00000339249.5 linkuse as main transcript	c.509C>T	p.Pro170Leu	missense_variant	3/5	1	NM_152695.6	ENSP00000339585	P1	Q6P9G9-1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111786

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33966

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000110

AC:

AN:

182490

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000401

AC:

AN:

1098177

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

363533

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

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:

0.0000499

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111786

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

33966

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

The c.509C>T (p.P170L) alteration is located in exon 3 (coding exon 2) of the ZNF449 gene. This alteration results from a C to T substitution at nucleotide position 509, causing the proline (P) at amino acid position 170 to be replaced by a leucine (L). 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

0.17

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.52

DEOGEN2

Benign

0.024

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.77

M_CAP

Benign

0.0045

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Benign

0.43

REVEL

Benign

0.016

Sift

Benign

0.086

Sift4G

Benign

0.72

Polyphen

0.014

Vest4

0.14

MVP

0.23

MPC

0.66

ClinPred

0.030

GERP RS

2.0

Varity_R

0.038

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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