14-21090961-G-A

Position:

• chr14-21090961-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016423.3(ZNF219):​c.1744C>T​(p.Pro582Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 7.1e-7 (0 hom.)
• Consequence: ZNF219 NM_016423.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.439

Genes affected

ZNF219 (HGNC:13011): (zinc finger protein 219) This gene is a member of the Kruppel-like zinc finger gene family. The encoded protein functions as a transcriptional repressor of the high mobility group nucleosome binding domain 1 protein, which is associated with transcriptionally active chromatin. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072879046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF219	NM_016423.3	c.1744C>T	p.Pro582Ser	missense_variant	5/5	ENST00000360947.8	NP_057507.2
ZNF219	NM_001101672.2	c.1744C>T	p.Pro582Ser	missense_variant	5/5		NP_001095142.1
ZNF219	NM_001102454.2	c.1744C>T	p.Pro582Ser	missense_variant	5/5		NP_001095924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF219	ENST00000360947.8	c.1744C>T	p.Pro582Ser	missense_variant	5/5	1	NM_016423.3	ENSP00000354206.3
ZNF219	ENST00000421093.6	c.1744C>T	p.Pro582Ser	missense_variant	5/5	1		ENSP00000392401.2
ZNF219	ENST00000451119.6	c.1744C>T	p.Pro582Ser	missense_variant	5/5	5		ENSP00000388558.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399696 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692302

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: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000878 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.1744C>T (p.P582S) alteration is located in exon 5 (coding exon 4) of the ZNF219 gene. This alteration results from a C to T substitution at nucleotide position 1744, causing the proline (P) at amino acid position 582 to be replaced by a serine (S). 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	0.061
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	10
DANN	Benign	0.86
DEOGEN2	Benign	0.0036	T;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.073	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.26	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.76	T;T;T
Polyphen		0.020	B;B;B
Vest4		0.14
MutPred		0.20		Gain of phosphorylation at P582 (P = 0.0101);Gain of phosphorylation at P582 (P = 0.0101);Gain of phosphorylation at P582 (P = 0.0101);
MVP		0.043
MPC		0.80
ClinPred		0.16	T
GERP RS		2.0
Varity_R		0.058
gMVP		0.37

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: rs767139613; hg19: chr14-21559120;