19-11867791-C-T

Variant summary

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

The NM_001348719.2(ZNF439):​c.737C>T​(p.Pro246Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ZNF439
NM_001348719.2 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75
Variant links:
Genes affected
ZNF439 (HGNC:20873): (zinc finger protein 439) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.13760743).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF439NM_001348719.2 linkc.737C>T p.Pro246Leu missense_variant Exon 4 of 4 ENST00000682736.1 NP_001335648.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF439ENST00000682736.1 linkc.737C>T p.Pro246Leu missense_variant Exon 4 of 4 NM_001348719.2 ENSP00000506930.1 A0A804HI69
ZNF439ENST00000304030.2 linkc.722C>T p.Pro241Leu missense_variant Exon 3 of 3 1 ENSP00000305077.2 Q8NDP4
ZNF439ENST00000455282.1 linkc.314C>T p.Pro105Leu missense_variant Exon 3 of 3 1 ENSP00000395632.1 A0A0C4DG37
ZNF439ENST00000592534.1 linkn.120-15760C>T intron_variant Intron 1 of 1 3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251244
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135796
show subpopulations
Gnomad AFR exome
AF:
0.000246
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461796
Hom.:
0
Cov.:
32
AF XY:
0.0000303
AC XY:
22
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.722C>T (p.P241L) alteration is located in exon 3 (coding exon 3) of the ZNF439 gene. This alteration results from a C to T substitution at nucleotide position 722, causing the proline (P) at amino acid position 241 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
Uncertain
0.44
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
15
DANN
Benign
0.94
DEOGEN2
Benign
0.13
.;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.060
T;T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
1.7
.;L
PrimateAI
Benign
0.29
T
PROVEAN
Pathogenic
-9.2
D;D
REVEL
Benign
0.098
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.012
D;D
Polyphen
1.0
.;D
Vest4
0.15
MVP
0.49
MPC
0.15
ClinPred
0.45
T
GERP RS
0.57
Varity_R
0.30
gMVP
0.014

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.

Other links and lift over

dbSNP: rs374360870; hg19: chr19-11978606; COSMIC: COSV58309291; COSMIC: COSV58309291; API