rs3885179

Positions:

• chr19-14717018-C-A
• chr19-14717018-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032433.4(ZNF333):​c.752C>A​(p.Ala251Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,611,552 control chromosomes in the GnomAD database, including 1,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (145 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1504 hom.)
• Consequence: ZNF333 NM_032433.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

Genes affected

ZNF333 (HGNC:15624): (zinc finger protein 333) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040817857).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF333	NM_032433.4	c.752C>A	p.Ala251Glu	missense_variant	10/12	ENST00000292530.11	NP_115809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF333	ENST00000292530.11	c.752C>A	p.Ala251Glu	missense_variant	10/12	1	NM_032433.4	ENSP00000292530.5

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6285 AN: 152090 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0384

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0659

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0454 AC: 11228 AN: 247418 Hom.: 348 AF XY: 0.0472 AC XY: 6305 AN XY: 133542

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.0648

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.0398

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0424 AC: 61805 AN: 1459344 Hom.: 1504 Cov.: 30 AF XY: 0.0431 AC XY: 31244 AN XY: 725690

Gnomad4 AFR exome AF: 0.0384

Gnomad4 AMR exome AF: 0.0145

Gnomad4 ASJ exome AF: 0.0318

Gnomad4 EAS exome AF: 0.0957

Gnomad4 SAS exome AF: 0.0651

Gnomad4 FIN exome AF: 0.0575

Gnomad4 NFE exome AF: 0.0393

Gnomad4 OTH exome AF: 0.0447

GnomAD4 genome AF: 0.0413 AC: 6288 AN: 152208 Hom.: 145 Cov.: 32 AF XY: 0.0430 AC XY: 3196 AN XY: 74410

Gnomad4 AFR AF: 0.0381

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0384

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.0657

Gnomad4 FIN AF: 0.0540

Gnomad4 NFE AF: 0.0400

Gnomad4 OTH AF: 0.0402

Alfa AF: 0.0398 Hom.: 186

Bravo AF: 0.0390

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0410 AC: 158

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.0408 AC: 351

ExAC AF: 0.0468 AC: 5678

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.9
DANN	Benign	0.90
DEOGEN2	Benign	0.00083	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.095	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.040
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.35	T;T
Polyphen		0.17	.;B
Vest4		0.19
MPC		0.44
ClinPred		0.038	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs3885179; hg19: chr19-14827830; COSMIC: COSV52885432; COSMIC: COSV52885432;