19-44386515-A-G

Position:

• chr19-44386515-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152354.6(ZNF285):​c.1730T>C​(p.Leu577Pro) 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 pathogenic outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF285 NM_152354.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

Genes affected

ZNF285 (HGNC:13079): (zinc finger protein 285) 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 active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF285	NM_152354.6	c.1730T>C	p.Leu577Pro	missense_variant	4/4	ENST00000614994.5	NP_689567.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF285	ENST00000614994.5	c.1730T>C	p.Leu577Pro	missense_variant	4/4	1	NM_152354.6	ENSP00000483662	P2
ZNF285	ENST00000591679.5	c.1751T>C	p.Leu584Pro	missense_variant	5/5	4		ENSP00000464788	A2
ZNF285	ENST00000544719.6	c.1730T>C	p.Leu577Pro	missense_variant	4/4	5		ENSP00000439431	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461602 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727074

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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.1730T>C (p.L577P) alteration is located in exon 4 (coding exon 3) of the ZNF285 gene. This alteration results from a T to C substitution at nucleotide position 1730, causing the leucine (L) at amino acid position 577 to be replaced by a proline (P). 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	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Uncertain	1.0
Eigen	Benign	0.0069
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.099	N
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.0034	T
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.61	D;N;N;N
REVEL	Benign	0.10
Sift4G	Uncertain	0.011	D;D;D
Vest4		0.40
MutPred		0.80		Loss of stability (P = 0.0181);Loss of stability (P = 0.0181);.;
MVP		0.43
ClinPred		0.76	D
GERP RS		2.1
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44890677;