Genetic Variant ZNF580:p.Ala146Thr (chr19-55642944-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207115.2(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. 14/22 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
NM_207115.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.369

Publications

0 publications found

Variant links:

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]

ZNF580 links:

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]

ZNF581 links:

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

CCDC106 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
ZNF580	NM_207115.2 link	c.436G>A	p.Ala146Thr	missense_variant	Exon 2 of 2	ENST00000325333.10	NP_996998.1	Q9UK33
ZNF580	NM_001163423.2 link	c.436G>A	p.Ala146Thr	missense_variant	Exon 2 of 2		NP_001156895.1	Q9UK33
ZNF580	NM_016202.2 link	c.436G>A	p.Ala146Thr	missense_variant	Exon 1 of 1		NP_057286.1	Q9UK33
ZNF581	XM_017026867.2 link	c.-19-1609G>A		intron_variant	Intron 1 of 1		XP_016882356.1	Q9P0T4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF580	ENST00000325333.10 link	c.436G>A	p.Ala146Thr	missense_variant	Exon 2 of 2	1	NM_207115.2	ENSP00000320050.4		Q9UK33

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1285558

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

629744

African (AFR)

AF:

0.00

AC:

AN:

25766

American (AMR)

AF:

0.00

AC:

AN:

19934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19340

East Asian (EAS)

AF:

0.00

AC:

AN:

29474

South Asian (SAS)

AF:

0.00

AC:

AN:

63564

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4808

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1030226

Other (OTH)

AF:

0.00

AC:

AN:

52946

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

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

LIST_S2

Benign

0.39

.;.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.97

L;L;L

PhyloP100

0.37

PrimateAI

Pathogenic

0.81

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

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.045

gMVP

0.13

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over