chr19-12015545-C-T

Variant names:

• chr19-12015545-C-T
• rs765613039
• NM_001308348.2:c.1313G>A

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.1313G>A​(p.Gly438Asp) 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 1,461,846 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. G438V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF433 NM_001308348.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06901336).

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.1313G>A	p.Gly438Asp	missense	Exon 4 of 4	NP_001295277.1	F8VTV7
	ZNF433	NM_001080411.3		c.1322G>A	p.Gly441Asp	missense	Exon 4 of 4	NP_001073880.1	Q8N7K0-1
	ZNF433	NM_001308346.2		c.1319G>A	p.Gly440Asp	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.1313G>A	p.Gly438Asp	missense	Exon 4 of 4	ENSP00000448099.2	F8VTV7
	ZNF433	ENST00000478765.6	TSL:1	c.1355G>A	p.Gly452Asp	missense	Exon 3 of 3	ENSP00000447951.2	C9JQA6
	ZNF433	ENST00000419886.7	TSL:1	c.1217G>A	p.Gly406Asp	missense	Exon 5 of 5	ENSP00000393416.2	Q8N7K0-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.8
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.000060	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.063
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.018
Sift	Benign	0.040	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.29	B
Vest4		0.17
MutPred		0.38		Loss of methylation at R442 (P = 0.0367)
MVP		0.088
MPC		0.11
ClinPred		0.20	T
GERP RS		-2.4
Varity_R		0.063
gMVP		0.069
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: rs765613039; hg19: chr19-12126360;