chr19-12015335-C-T

Variant names:

• chr19-12015335-C-T
• rs771710472
• NM_001308348.2:c.1523G>A

Variant summary

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

The NM_001308348.2(ZNF433):​c.1523G>A​(p.Cys508Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000074 (0 hom.)
• Consequence: ZNF433 NM_001308348.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1523G>A	p.Cys508Tyr	missense	Exon 4 of 4	NP_001295277.1	F8VTV7
	ZNF433	NM_001080411.3		c.1532G>A	p.Cys511Tyr	missense	Exon 4 of 4	NP_001073880.1	Q8N7K0-1
	ZNF433	NM_001308346.2		c.1529G>A	p.Cys510Tyr	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.1523G>A	p.Cys508Tyr	missense	Exon 4 of 4	ENSP00000448099.2	F8VTV7
	ZNF433	ENST00000478765.6	TSL:1	c.1565G>A	p.Cys522Tyr	missense	Exon 3 of 3	ENSP00000447951.2	C9JQA6
	ZNF433	ENST00000419886.7	TSL:1	c.1427G>A	p.Cys476Tyr	missense	Exon 5 of 5	ENSP00000393416.2	Q8N7K0-2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151982 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250502 AF XY: 0.0000221

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: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 49 AN XY: 727242

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: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

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: 0.0000917 AC: 102 AN: 1112006

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 151982 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74214

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.32
MPC		0.31
ClinPred		1.0	D
GERP RS		1.2
Varity_R		0.69
gMVP		0.067
Mutation Taster		=72/28	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: rs771710472; hg19: chr19-12126150;