chr19-55642944-G-A

Position:

• chr19-55642944-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000325333.10(ZNF580):​c.436G>A​(p.Ala146Thr) 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. 13/21 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ZNF580 ENST00000325333.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.369

Genes affected

ZNF580 (HGNC:29473): (zinc finger protein 580) Enables sequence-specific double-stranded DNA binding activity. Involved in several processes, including cellular response to hydrogen peroxide; positive regulation of cell migration; and positive regulation of interleukin-8 production. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF581 (HGNC:25017): (zinc finger protein 581) Predicted to enable DNA-binding transcription factor activity 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]

CCDC106 (HGNC:30181): (coiled-coil domain containing 106) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06225747).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF580	NM_207115.2	c.436G>A	p.Ala146Thr	missense_variant	2/2	ENST00000325333.10	NP_996998.1
ZNF580	NM_001163423.2	c.436G>A	p.Ala146Thr	missense_variant	2/2		NP_001156895.1
ZNF580	NM_016202.2	c.436G>A	p.Ala146Thr	missense_variant	1/1		NP_057286.1
ZNF581	XM_017026867.2	c.-19-1609G>A		intron_variant			XP_016882356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF580	ENST00000325333.10	c.436G>A	p.Ala146Thr	missense_variant	2/2	1	NM_207115.2	ENSP00000320050	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1285558 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 629744

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: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Apr 06, 2024

The c.436G>A (p.A146T) alteration is located in exon 1 (coding exon 1) of the ZNF580 gene. This alteration results from a G to A substitution at nucleotide position 436, causing the alanine (A) at amino acid position 146 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0052	T;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.39	.;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.062	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.38	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.13	B;B;B
Vest4		0.098
MutPred		0.33		Gain of glycosylation at A146 (P = 0.0135);Gain of glycosylation at A146 (P = 0.0135);Gain of glycosylation at A146 (P = 0.0135);
MVP		0.13
MPC		1.4
ClinPred		0.25	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.045
gMVP		0.13

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: rs1982620797; hg19: chr19-56154310;