Variant 19-55644965-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016535.4(ZNF581):c.394C>T(p.Arg132Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ZNF581
NM_016535.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.401

Variant links:

Genes affected

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 made for transcript

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/exons	MANE	Protein	UniProt
ZNF581	NM_016535.4 linkuse as main transcript	c.394C>T	p.Arg132Trp	missense_variant	2/2	ENST00000270451.6	NP_057619.1	Q9P0T4
ZNF581	XM_017026867.2 linkuse as main transcript	c.394C>T	p.Arg132Trp	missense_variant	2/2		XP_016882356.1	Q9P0T4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF581	ENST00000270451.6 linkuse as main transcript	c.394C>T	p.Arg132Trp	missense_variant	2/2	1	NM_016535.4	ENSP00000270451.4		Q9P0T4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723866

show subpopulations

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:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2024

The c.394C>T (p.R132W) alteration is located in exon 2 (coding exon 1) of the ZNF581 gene. This alteration results from a C to T substitution at nucleotide position 394, causing the arginine (R) at amino acid position 132 to be replaced by a tryptophan (W). 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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.45

.;T;.;T

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.49

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.7

M;.;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.2

.;.;D;.

REVEL

Benign

0.26

Sift

Pathogenic

0.0

.;.;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.34

MutPred

0.55

Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);Loss of disorder (P = 0.0017);

MVP

0.40

MPC

1.1

ClinPred

0.99

GERP RS

-1.5

Varity_R

0.48

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over