Genetic Variant ZNF653:p.Ser536Phe (chr19-11484105-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138783.4(ZNF653):c.1607C>T(p.Ser536Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF653
NM_138783.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.72

Publications

0 publications found

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]

ZNF653 links:

ENSG00000267477 (HGNC:):

ENSG00000267477 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF653	NM_138783.4 link	c.1607C>T	p.Ser536Phe	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
ZNF653	ENST00000293771.10 link	c.1607C>T	p.Ser536Phe	missense_variant	Exon 8 of 9	1	NM_138783.4	ENSP00000293771.3		Q96CK0
ENSG00000267477	ENST00000585656.1 link	n.469+11845C>T		intron_variant	Intron 3 of 4	5		ENSP00000466387.1		K7EM74

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693648

African (AFR)

AF:

0.00

AC:

AN:

31836

American (AMR)

AF:

0.00

AC:

AN:

36446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36252

South Asian (SAS)

AF:

0.00

AC:

AN:

79672

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082394

Other (OTH)

AF:

0.00

AC:

AN:

58258

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1607C>T (p.S536F) alteration is located in exon 8 (coding exon 8) of the ZNF653 gene. This alteration results from a C to T substitution at nucleotide position 1607, causing the serine (S) at amino acid position 536 to be replaced by a phenylalanine (F). 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

0.97

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

PhyloP100

5.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.59

MutPred

0.64

Loss of disorder (P = 0.0139);

MVP

0.61

MPC

1.9

ClinPred

1.0

GERP RS

4.6

Varity_R

0.85

gMVP

0.66

Mutation Taster

=53/47

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over