19-57776639-C-A

Variant names:

• chr19-57776639-C-A
• NM_017652.4:c.133C>A

Variant summary

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

The NM_017652.4(ZNF586):​c.133C>A​(p.Leu45Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ZNF586 NM_017652.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.351

Genes affected

ZNF586 (HGNC:25949): (zinc finger protein 586) 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF586	NM_017652.4	c.133C>A	p.Leu45Met	missense_variant	Exon 2 of 3	ENST00000396154.7	NP_060122.2
ZNF586	NM_001204814.2	c.4C>A	p.Leu2Met	missense_variant	Exon 3 of 4		NP_001191743.1
ZNF586	NM_001077426.3	c.37-2112C>A		intron_variant	Intron 1 of 1		NP_001070894.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF586	ENST00000396154.7	c.133C>A	p.Leu45Met	missense_variant	Exon 2 of 3	1	NM_017652.4	ENSP00000379458.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133C>A (p.L45M) alteration is located in exon 2 (coding exon 2) of the ZNF586 gene. This alteration results from a C to A substitution at nucleotide position 133, causing the leucine (L) at amino acid position 45 to be replaced by a methionine (M). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	.;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.0022	T
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	.;D
Vest4		0.33
MutPred		0.78		.;Gain of helix (P = 0.132);
MVP		0.088
MPC		0.39
ClinPred		0.72	D
GERP RS		0.70
Varity_R		0.49
gMVP		0.046

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr19-58288007;