19-52613457-C-T

Variant names:

• chr19-52613457-C-T
• rs1568522955
• ENST00000301096.8:c.1108G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018300.4(ZNF83):​c.1108G>A​(p.Glu370Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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)
• Consequence: ZNF83 NM_018300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2677399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF83	NM_001105549.2	c.1108G>A	p.Glu370Lys	missense_variant	Exon 6 of 6		NP_001099019.1
ZNF83	NM_001105550.2	c.1108G>A	p.Glu370Lys	missense_variant	Exon 5 of 5		NP_001099020.1
ZNF83	NM_001105551.2	c.1108G>A	p.Glu370Lys	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.1108G>A	p.Glu370Lys	missense_variant	Exon 3 of 3	3		ENSP00000301096.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1108G>A (p.E370K) 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 1108, causing the glutamic acid (E) at amino acid position 370 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	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;T;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.22	.;T;.;.;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L;L;L
PROVEAN	Uncertain	-3.7	D;D;.;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.23
MutPred		0.54		Gain of methylation at E370 (P = 0.0056);Gain of methylation at E370 (P = 0.0056);Gain of methylation at E370 (P = 0.0056);Gain of methylation at E370 (P = 0.0056);Gain of methylation at E370 (P = 0.0056);
MVP		0.45
MPC		0.40
ClinPred		0.89	D
GERP RS		1.1
Varity_R		0.30
gMVP		0.020

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: rs1568522955; hg19: chr19-53116710; COSMIC: COSV99991630; COSMIC: COSV99991630;