Genetic Variant ZBED3:p.Glu126Lys (chr5-77077503-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032367.4(ZBED3):c.376G>A(p.Glu126Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000997 in 1,193,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

ZBED3
NM_032367.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.40

Variant links:

Genes affected

ZBED3 (HGNC:20711): (zinc finger BED-type containing 3) This gene belongs to a class of genes that arose through hAT DNA transposition and that encode regulatory proteins. This gene is upregulated in lung cancer tissues, where the encoded protein causes an accumulation of beta-catenin and enhanced lung cancer cell invasion. In addition, the encoded protein can be secreted and be involved in resistance to insulin. [provided by RefSeq, Jul 2016]

ZBED3 links:

ENSG00000285000 (HGNC:):

ENSG00000285000 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37205756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED3	NM_032367.4 link	c.376G>A	p.Glu126Lys	missense_variant	Exon 3 of 3	ENST00000255198.3	NP_115743.1	Q96IU2
ZBED3	NM_001329564.2 link	c.376G>A	p.Glu126Lys	missense_variant	Exon 2 of 2		NP_001316493.1	Q96IU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBED3	ENST00000255198.3 link	c.376G>A	p.Glu126Lys	missense_variant	Exon 3 of 3	1	NM_032367.4	ENSP00000255198.2	Q96IU2
ENSG00000285000	ENST00000646704.1 link	n.1809+15701C>T		intron_variant	Intron 13 of 15			ENSP00000495089.1	A0A2R8YFF1
ZBED3	ENST00000511587.1 link	c.376G>A	p.Glu126Lys	missense_variant	Exon 2 of 2	3		ENSP00000427487.1	D6RIC4

Frequencies

GnomAD3 genomes

AF:

0.0000934

AC:

AN:

149942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000664

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000102

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

105

AN:

1043124

Hom.:

Cov.:

AF XY:

0.0000989

AC XY:

AN XY:

495374

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:

0.0000509

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000934

AC:

AN:

149942

Hom.:

Cov.:

AF XY:

0.0000821

AC XY:

AN XY:

73124

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.0000664

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000102

Gnomad4 NFE

AF:

0.000164

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000324

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.376G>A (p.E126K) alteration is located in exon 3 (coding exon 1) of the ZBED3 gene. This alteration results from a G to A substitution at nucleotide position 376, causing the glutamic acid (E) at amino acid position 126 to be replaced by a lysine (K). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

T;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.65

T;T

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.99

D;.

Vest4

0.45

MutPred

0.15

Gain of ubiquitination at E126 (P = 0.009);Gain of ubiquitination at E126 (P = 0.009);

MVP

0.30

MPC

1.7

ClinPred

0.98

GERP RS

4.0

Varity_R

0.48

gMVP

0.17

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