19-52613643-A-G

Variant names:

• chr19-52613643-A-G
• rs878921853
• ENST00000301096.8:c.922T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018300.4(ZNF83):​c.922T>C​(p.Trp308Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZNF83 NM_018300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.110

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031111747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF83	NM_001105549.2	c.922T>C	p.Trp308Arg	missense_variant	Exon 6 of 6		NP_001099019.1
ZNF83	NM_001105550.2	c.922T>C	p.Trp308Arg	missense_variant	Exon 5 of 5		NP_001099020.1
ZNF83	NM_001105551.2	c.922T>C	p.Trp308Arg	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.922T>C	p.Trp308Arg	missense_variant	Exon 3 of 3	3		ENSP00000301096.3

Frequencies

GnomAD3 genomes AF: 0.0000803 AC: 12 AN: 149518 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461596 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000803 AC: 12 AN: 149518 Hom.: 0 Cov.: 33 AF XY: 0.0000959 AC XY: 7 AN XY: 72980

Gnomad4 AFR AF: 0.0000248

Gnomad4 AMR AF: 0.000666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.922T>C (p.W308R) alteration is located in exon 6 (coding exon 1) of the ZNF83 gene. This alteration results from a T to C substitution at nucleotide position 922, causing the tryptophan (W) at amino acid position 308 to be replaced by an arginine (R). 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	Benign	0.32
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.047
DANN	Benign	0.27
DEOGEN2	Benign	0.0013	T;T;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.22	.;T;.;.;.
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.031	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;N;N;N;N
PROVEAN	Benign	2.9	N;N;.;N;N
REVEL	Benign	0.019
Sift	Benign	0.43	T;T;.;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.030
MutPred		0.57		Gain of disorder (P = 7e-04);Gain of disorder (P = 7e-04);Gain of disorder (P = 7e-04);Gain of disorder (P = 7e-04);Gain of disorder (P = 7e-04);
MVP		0.17
MPC		0.11
ClinPred		0.028	T
GERP RS		-3.2
Varity_R		0.020
gMVP		0.14

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: rs878921853; hg19: chr19-53116896;