19-11484096-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_138783.4(ZNF653):​c.1616G>A​(p.Arg539Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

ZNF653
NM_138783.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68
Variant links:
Genes affected
ZNF653 (HGNC:25196): (zinc finger protein 653) Enables AF-2 domain binding activity and transcription corepressor activity. Involved in extracellular negative regulation of signal transduction and negative regulation of nucleic acid-templated transcription. Predicted to be located in extracellular region. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29828352).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF653NM_138783.4 linkc.1616G>A p.Arg539Lys missense_variant Exon 8 of 9 ENST00000293771.10 NP_620138.2 Q96CK0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF653ENST00000293771.10 linkc.1616G>A p.Arg539Lys missense_variant Exon 8 of 9 1 NM_138783.4 ENSP00000293771.3 Q96CK0
ENSG00000267477ENST00000585656.1 linkn.469+11854G>A intron_variant Intron 3 of 4 5 ENSP00000466387.1 K7EM74

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1616G>A (p.R539K) alteration is located in exon 8 (coding exon 8) of the ZNF653 gene. This alteration results from a G to A substitution at nucleotide position 1616, causing the arginine (R) at amino acid position 539 to be replaced by a lysine (K). 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
Pathogenic
0.98
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.020
T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.30
T
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
1.3
L
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.78
N
REVEL
Benign
0.19
Sift
Uncertain
0.012
D
Sift4G
Uncertain
0.031
D
Polyphen
1.0
D
Vest4
0.28
MutPred
0.68
Gain of methylation at R539 (P = 0.0184);
MVP
0.49
MPC
1.8
ClinPred
0.80
D
GERP RS
4.8
Varity_R
0.57
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-11594911; API