Genetic Variant ZBED5:p.Ala558Thr (chr11-10853274-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001143667.2(ZBED5):c.1672G>A(p.Ala558Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,551,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

ZBED5
NM_001143667.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0910

Variant links:

Genes affected

ZBED5 (HGNC:30803): (zinc finger BED-type containing 5) This gene is unusual in that its coding sequence is mostly derived from Charlie-like DNA transposon; however, it does not appear to be an active DNA transposon as it is not flanked by terminal inverted repeats. The encoded protein is conserved among the mammalian Laurasiatheria branch. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2009]

ZBED5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.02237773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED5	NM_001143667.2 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 3 of 3	ENST00000413761.7	NP_001137139.1	Q49AG3
ZBED5	NM_021211.4 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 3 of 3		NP_067034.2	Q49AG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBED5	ENST00000413761.7 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 3 of 3	1	NM_001143667.2	ENSP00000415939.2	Q49AG3
ZBED5	ENST00000432999.6 link	c.1672G>A	p.Ala558Thr	missense_variant	Exon 3 of 3	1		ENSP00000398106.2	Q49AG3
ZBED5	ENST00000525350.5 link	n.75+2870G>A		intron_variant	Intron 1 of 4	2
ZBED5	ENST00000533925.5 link	n.326+2870G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

153190

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

80982

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00133

Gnomad SAS exome

AF:

0.0000879

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000829

AC:

116

AN:

1399298

Hom.:

Cov.:

AF XY:

0.0000898

AC XY:

AN XY:

690140

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.00288

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000649

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000447

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1672G>A (p.A558T) alteration is located in exon 3 (coding exon 1) of the ZBED5 gene. This alteration results from a G to A substitution at nucleotide position 1672, causing the alanine (A) at amino acid position 558 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

0.075

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.6

DANN

Benign

0.85

DEOGEN2

Benign

0.00058

T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.17

.;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.30

N;N

REVEL

Benign

0.050

Sift

Benign

0.47

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.83

P;P

Vest4

0.066

MutPred

0.26

Gain of ubiquitination at K562 (P = 0.1062);Gain of ubiquitination at K562 (P = 0.1062);

MVP

0.040

ClinPred

0.034

GERP RS

2.8

Varity_R

0.020

gMVP

0.25

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