19-52613348-C-T

Variant names:

• chr19-52613348-C-T
• rs1370412235
• ENST00000301096.8:c.1217G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018300.4(ZNF83):​c.1217G>A​(p.Cys406Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,718 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: 0.0000062 (0 hom.)
• Consequence: ZNF83 NM_018300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF83	NM_001105549.2	c.1217G>A	p.Cys406Tyr	missense_variant	Exon 6 of 6		NP_001099019.1
ZNF83	NM_001105550.2	c.1217G>A	p.Cys406Tyr	missense_variant	Exon 5 of 5		NP_001099020.1
ZNF83	NM_001105551.2	c.1217G>A	p.Cys406Tyr	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.1217G>A	p.Cys406Tyr	missense_variant	Exon 3 of 3	3		ENSP00000301096.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251302 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135814

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461718 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727162

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1217G>A (p.C406Y) alteration is located in exon 6 (coding exon 1) of the ZNF83 gene. This alteration results from a G to A substitution at nucleotide position 1217, causing the cysteine (C) at amino acid position 406 to be replaced by a tyrosine (Y). 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	0.88
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T;T;T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	-0.0095
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.32	.;T;.;.;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H
PROVEAN	Pathogenic	-9.7	D;D;.;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.33
MutPred		0.70		Gain of phosphorylation at C406 (P = 0.0274);Gain of phosphorylation at C406 (P = 0.0274);Gain of phosphorylation at C406 (P = 0.0274);Gain of phosphorylation at C406 (P = 0.0274);Gain of phosphorylation at C406 (P = 0.0274);
MVP		0.86
MPC		0.49
ClinPred		0.96	D
GERP RS		2.1
Varity_R		0.85
gMVP		0.077

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: rs1370412235; hg19: chr19-53116601;