19-11483833-C-G

Variant names:

• chr19-11483833-C-G
• rs1379374014
• NM_138783.4:c.1697G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138783.4(ZNF653):​c.1697G>C​(p.Arg566Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000352 in 1,422,028 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. R566Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ZNF653 NM_138783.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.86
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138783.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF653	NM_138783.4	MANE Select	c.1697G>C	p.Arg566Pro	missense	Exon 9 of 9	NP_620138.2	Q96CK0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF653	ENST00000293771.10	TSL:1 MANE Select	c.1697G>C	p.Arg566Pro	missense	Exon 9 of 9	ENSP00000293771.3	Q96CK0
	ENSG00000267477	ENST00000585656.1	TSL:5	n.469+12117G>C		intron	N/A	ENSP00000466387.1	K7EM74
	ZNF653	ENST00000937056.1		c.1085G>C	p.Arg362Pro	missense	Exon 8 of 8	ENSP00000607115.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1422028 Hom.: 0 Cov.: 34 AF XY: 0.00000566 AC XY: 4 AN XY: 706298

African (AFR) AF: 0.00 AC: 0 AN: 32488

American (AMR) AF: 0.00 AC: 0 AN: 42692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.00 AC: 0 AN: 37110

South Asian (SAS) AF: 0.00 AC: 0 AN: 84978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.00000459 AC: 5 AN: 1088860

Other (OTH) AF: 0.00 AC: 0 AN: 57874

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.57		Loss of MoRF binding (P = 0.015)
MVP		0.63
MPC		2.2
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.84
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs1379374014; hg19: chr19-11594648;