19-52613420-A-C

Variant names:

• chr19-52613420-A-C
• rs2060177998
• ENST00000301096.8:c.1145T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018300.4(ZNF83):​c.1145T>G​(p.Phe382Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF83 NM_018300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

Genes affected

ZNF83 (HGNC:13158): (zinc finger protein 83) 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000290073 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF83	NM_001105549.2	c.1145T>G	p.Phe382Cys	missense_variant	Exon 6 of 6		NP_001099019.1
ZNF83	NM_001105550.2	c.1145T>G	p.Phe382Cys	missense_variant	Exon 5 of 5		NP_001099020.1
ZNF83	NM_001105551.2	c.1145T>G	p.Phe382Cys	missense_variant	Exon 5 of 5		NP_001099021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF83	ENST00000301096.8	c.1145T>G	p.Phe382Cys	missense_variant	Exon 3 of 3	3		ENSP00000301096.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461422 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1145T>G (p.F382C) alteration is located in exon 6 (coding exon 1) of the ZNF83 gene. This alteration results from a T to G substitution at nucleotide position 1145, causing the phenylalanine (F) at amino acid position 382 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	.;T;.;.;.
M_CAP	Benign	0.0062	T
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.3	M;M;M;M;M
PROVEAN	Pathogenic	-7.5	D;D;.;D;D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.46
MutPred		0.76		Gain of ubiquitination at K380 (P = 0.0822);Gain of ubiquitination at K380 (P = 0.0822);Gain of ubiquitination at K380 (P = 0.0822);Gain of ubiquitination at K380 (P = 0.0822);Gain of ubiquitination at K380 (P = 0.0822);
MVP		0.69
MPC		0.46
ClinPred		0.97	D
GERP RS		2.1
Varity_R		0.68
gMVP		0.081

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

Publications

LitVar

Other links and lift over

dbSNP: rs2060177998; hg19: chr19-53116673;