19-12015383-C-G

Variant names:

• chr19-12015383-C-G
• rs576813648
• NM_001308348.2:c.1475G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001308348.2(ZNF433):​c.1475G>C​(p.Arg492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R492I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF433 NM_001308348.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -7.16
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07672194).

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.1475G>C	p.Arg492Thr	missense	Exon 4 of 4	NP_001295277.1	F8VTV7
	ZNF433	NM_001080411.3		c.1484G>C	p.Arg495Thr	missense	Exon 4 of 4	NP_001073880.1	Q8N7K0-1
	ZNF433	NM_001308346.2		c.1481G>C	p.Arg494Thr	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.1475G>C	p.Arg492Thr	missense	Exon 4 of 4	ENSP00000448099.2	F8VTV7
	ZNF433	ENST00000478765.6	TSL:1	c.1517G>C	p.Arg506Thr	missense	Exon 3 of 3	ENSP00000447951.2	C9JQA6
	ZNF433	ENST00000419886.7	TSL:1	c.1379G>C	p.Arg460Thr	missense	Exon 5 of 5	ENSP00000393416.2	Q8N7K0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250196 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33476

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.054
DANN	Benign	0.61
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.00096	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-7.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.033
Sift	Benign	0.68	T
Sift4G	Benign	0.75	T
Polyphen		0.71	P
Vest4		0.23
MutPred		0.30		Gain of phosphorylation at R495 (P = 0.0271)
MVP		0.10
MPC		0.055
ClinPred		0.14	T
GERP RS		-2.4
Varity_R		0.039
gMVP		0.033
Mutation Taster		=99/1	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: rs576813648; hg19: chr19-12126198;