19-12015159-C-G

Variant names:

• chr19-12015159-C-G
• rs1427750923
• NM_001308348.2:c.1699G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001308348.2(ZNF433):​c.1699G>C​(p.Ala567Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. A567T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF433 NM_001308348.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.36
• Publications: 0 publications found

Genes affected

ZNF433 (HGNC:20811): (zinc finger protein 433) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000286098 (HGNC:):

ZNF433-AS1 (HGNC:53776): (ZNF433 and ZNF878 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35978013).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001308348.2. 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
	ZNF433	NM_001308348.2	MANE Select	c.1699G>C	p.Ala567Pro	missense	Exon 4 of 4	NP_001295277.1	F8VTV7
	ZNF433	NM_001080411.3		c.1708G>C	p.Ala570Pro	missense	Exon 4 of 4	NP_001073880.1	Q8N7K0-1
	ZNF433	NM_001308346.2		c.1705G>C	p.Ala569Pro	missense	Exon 5 of 5	NP_001295275.1	F8W0C9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF433	ENST00000550507.7	TSL:2 MANE Select	c.1699G>C	p.Ala567Pro	missense	Exon 4 of 4	ENSP00000448099.2	F8VTV7
	ZNF433	ENST00000478765.6	TSL:1	c.1741G>C	p.Ala581Pro	missense	Exon 3 of 3	ENSP00000447951.2	C9JQA6
	ZNF433	ENST00000419886.7	TSL:1	c.1603G>C	p.Ala535Pro	missense	Exon 5 of 5	ENSP00000393416.2	Q8N7K0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461728 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-5.4
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.079
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.64		Gain of ubiquitination at K565 (P = 0.0539)
MVP		0.19
MPC		0.30
ClinPred		0.86	D
GERP RS		0.29
Varity_R		0.52
gMVP		0.046
Mutation Taster		=95/5	polymorphism

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: rs1427750923; hg19: chr19-12125974;