19-11484096-C-T

Variant names:

• chr19-11484096-C-T
• NM_138783.4:c.1616G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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]

ENSG00000267477 (HGNC:):

ACMG classification

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
ZNF653	NM_138783.4	c.1616G>A	p.Arg539Lys	missense_variant	Exon 8 of 9	ENST00000293771.10	NP_620138.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF653	ENST00000293771.10	c.1616G>A	p.Arg539Lys	missense_variant	Exon 8 of 9	1	NM_138783.4	ENSP00000293771.3
ENSG00000267477	ENST00000585656.1	n.469+11854G>A		intron_variant	Intron 3 of 4	5		ENSP00000466387.1

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

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;