Genetic Variant ZBED5:p.Ala652Thr (chr11-10852992-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.1954G>A(p.Ala652Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,551,348 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ZBED5
NM_001143667.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.72

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=0.048999965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED5	NM_001143667.2 link	c.1954G>A	p.Ala652Thr	missense_variant	Exon 3 of 3	ENST00000413761.7	NP_001137139.1	Q49AG3
ZBED5	NM_021211.4 link	c.1954G>A	p.Ala652Thr	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.1954G>A	p.Ala652Thr	missense_variant	Exon 3 of 3	1	NM_001143667.2	ENSP00000415939.2	Q49AG3
ZBED5	ENST00000432999.6 link	c.1954G>A	p.Ala652Thr	missense_variant	Exon 3 of 3	1		ENSP00000398106.2	Q49AG3
ZBED5	ENST00000525350.5 link	n.75+3152G>A		intron_variant	Intron 1 of 4	2
ZBED5	ENST00000533925.5 link	n.327-2889G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152024

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000651

AC:

AN:

153548

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000884

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000207

AC:

AN:

1399324

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

690154

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:

0.0000269

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1954G>A (p.A652T) 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 1954, causing the alanine (A) at amino acid position 652 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

0.11

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.00077

T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.77

.;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.48

N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.22

N;N

REVEL

Benign

0.13

Sift

Benign

0.25

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.16

B;B

Vest4

0.40

MutPred

0.33

Gain of phosphorylation at A652 (P = 0.0323);Gain of phosphorylation at A652 (P = 0.0323);

MVP

0.088

ClinPred

0.29

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.32

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