chr19-52613222-C-T

Variant names:

• chr19-52613222-C-T
• rs143220585
• ENST00000301096.8:c.1343G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018300.4(ZNF83):​c.1343G>A​(p.Arg448Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,613,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ZNF83 NM_018300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.37

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]

ENSG00000269825 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02588728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF83	NM_001105549.2	c.1343G>A	p.Arg448Gln	missense_variant	Exon 6 of 6		NP_001099019.1
ZNF83	NM_001105550.2	c.1343G>A	p.Arg448Gln	missense_variant	Exon 5 of 5		NP_001099020.1
ZNF83	NM_001105551.2	c.1343G>A	p.Arg448Gln	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.1343G>A	p.Arg448Gln	missense_variant	Exon 3 of 3	3		ENSP00000301096.3

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151850 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.0000598 AC: 15 AN: 251008 AF XY: 0.0000295

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000139 AC: 203 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 726986

African (AFR) AF: 0.000120 AC: 4 AN: 33456

American (AMR) AF: 0.0000224 AC: 1 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000171 AC: 190 AN: 1111806

Other (OTH) AF: 0.0000994 AC: 6 AN: 60386

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151850 Hom.: 0 Cov.: 33 AF XY: 0.0000809 AC XY: 6 AN XY: 74180

African (AFR) AF: 0.000121 AC: 5 AN: 41310

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1343G>A (p.R448Q) 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 1343, causing the arginine (R) at amino acid position 448 to be replaced by a glutamine (Q). 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	0.082
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0080
DANN	Benign	0.15
DEOGEN2	Benign	0.00028	T;T;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.16	.;T;.;.;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N;N;N;N;N
PhyloP100		-1.4
PROVEAN	Benign	0.11	N;N;.;N;N
REVEL	Benign	0.013
Sift	Benign	1.0	T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.19	B;B;B;B;B
Vest4		0.024
MVP		0.12
MPC		0.27
ClinPred		0.032	T
GERP RS		-3.0
Varity_R		0.010
gMVP		0.012
Mutation Taster		=100/0	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

Publications

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Other links and lift over

dbSNP: rs143220585; hg19: chr19-53116475;