Genetic Variant ZNF83:p.Arg337Lys (chr19-52613555-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000301096.8(ZNF83):c.1010G>A(p.Arg337Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ZNF83
ENST00000301096.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.90

Publications

0 publications found

Variant links:

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]

ZNF83 links:

ENSG00000269825 (HGNC:):

ENSG00000269825 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ZNF83	NM_001105549.2 link	c.1010G>A	p.Arg337Lys	missense_variant	Exon 6 of 6	NP_001099019.1	P51522-1A0A024R4L3
ZNF83	NM_001105550.2 link	c.1010G>A	p.Arg337Lys	missense_variant	Exon 5 of 5	NP_001099020.1	P51522-1A0A024R4L3
ZNF83	NM_001105551.2 link	c.1010G>A	p.Arg337Lys	missense_variant	Exon 5 of 5	NP_001099021.1	P51522-1A0A024R4L3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF83	ENST00000301096.8 link	c.1010G>A	p.Arg337Lys	missense_variant	Exon 3 of 3	3		ENSP00000301096.3		P51522-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727198

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111984

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1010G>A (p.R337K) 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 1010, causing the arginine (R) at amino acid position 337 to be replaced by a lysine (K). 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

0.34

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.051

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0097

T;T;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.25

.;T;.;.;.

M_CAP

Benign

0.0038

MetaRNN

Uncertain

0.42

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.015

N;N;N;N;N

PhyloP100

-1.9

PROVEAN

Benign

-1.5

N;N;.;N;N

REVEL

Benign

0.052

Sift

Benign

0.10

T;T;.;T;T

Sift4G

Benign

0.094

T;T;T;T;T

Polyphen

1.0

D;D;D;D;D

Vest4

0.072

MutPred

0.75

Gain of methylation at R337 (P = 0.0143);Gain of methylation at R337 (P = 0.0143);Gain of methylation at R337 (P = 0.0143);Gain of methylation at R337 (P = 0.0143);Gain of methylation at R337 (P = 0.0143);

MVP

0.33

MPC

0.063

ClinPred

0.039

GERP RS

-0.35

Varity_R

0.051

gMVP

0.041

Mutation Taster

=100/0

polymorphism

(source)

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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chr19-52613555-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over