19-11483702-G-T

Variant names:

• chr19-11483702-G-T
• rs201563028
• NM_138783.4:c.1828C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138783.4(ZNF653):​c.1828C>A​(p.Pro610Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P610S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF653 NM_138783.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.53
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF653	NM_138783.4	c.1828C>A	p.Pro610Thr	missense_variant	Exon 9 of 9	ENST00000293771.10	NP_620138.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF653	ENST00000293771.10	c.1828C>A	p.Pro610Thr	missense_variant	Exon 9 of 9	1	NM_138783.4	ENSP00000293771.3
ENSG00000267477	ENST00000585656.1	n.469+12248C>A		intron_variant	Intron 3 of 4	5		ENSP00000466387.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460836 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726668

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111202

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.94	N
PhyloP100		6.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.32
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.32		Gain of phosphorylation at P610 (P = 0.0632);
MVP		0.49
MPC		1.9
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.57
gMVP		0.48
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs201563028; hg19: chr19-11594517;