14-21092053-G-A

Position:

• chr14-21092053-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_016423.3(ZNF219):​c.1244C>T​(p.Pro415Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,392,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000043 (0 hom.)
• Consequence: ZNF219 NM_016423.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33805823).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF219	NM_016423.3	c.1244C>T	p.Pro415Leu	missense_variant	3/5	ENST00000360947.8	NP_057507.2
ZNF219	NM_001101672.2	c.1244C>T	p.Pro415Leu	missense_variant	3/5		NP_001095142.1
ZNF219	NM_001102454.2	c.1244C>T	p.Pro415Leu	missense_variant	3/5		NP_001095924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF219	ENST00000360947.8	c.1244C>T	p.Pro415Leu	missense_variant	3/5	1	NM_016423.3	ENSP00000354206.3
ZNF219	ENST00000421093.6	c.1244C>T	p.Pro415Leu	missense_variant	3/5	1		ENSP00000392401.2
ZNF219	ENST00000451119.6	c.1244C>T	p.Pro415Leu	missense_variant	3/5	5		ENSP00000388558.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1392672 Hom.: 0 Cov.: 32 AF XY: 0.00000582 AC XY: 4 AN XY: 686834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000283

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000371

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Oct 26, 2022

The c.1244C>T (p.P415L) alteration is located in exon 3 (coding exon 2) of the ZNF219 gene. This alteration results from a C to T substitution at nucleotide position 1244, causing the proline (P) at amino acid position 415 to be replaced by a leucine (L). 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	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0054	T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.012	D;D;D
Sift4G	Benign	0.32	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.58
MutPred		0.31		Gain of MoRF binding (P = 0.0731);Gain of MoRF binding (P = 0.0731);Gain of MoRF binding (P = 0.0731);
MVP		0.082
MPC		1.9
ClinPred		0.76	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1419564822; hg19: chr14-21560212;