22-49883677-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014838.3(ZBED4):c.15G>C(p.Leu5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,583,964 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000092 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0000063 ( 0 hom. )

Consequence

ZBED4
NM_014838.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.298

Publications

0 publications found

Variant links:

Genes affected

ZBED4 (HGNC:20721): (zinc finger BED-type containing 4) Enables identical protein binding activity. Predicted to be involved in positive regulation of transcription by RNA polymerase II. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZBED4 links:

ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]

ALG12 Gene-Disease associations (from GenCC):

ALG12-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ALG12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02900207).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED4	NM_014838.3 link	c.15G>C	p.Leu5Phe	missense_variant	Exon 2 of 2	ENST00000216268.6	NP_055653.2	O75132

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBED4	ENST00000216268.6 link	c.15G>C	p.Leu5Phe	missense_variant	Exon 2 of 2	1	NM_014838.3	ENSP00000216268.4	O75132
ZBED4	ENST00000850559.1 link	c.15G>C	p.Leu5Phe	missense_variant	Exon 2 of 2			ENSP00000520851.1
ZBED4	ENST00000850560.1 link	n.260+199G>C		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000955

GnomAD2 exomes

AF:

0.0000127

AC:

AN:

236468

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000629

AC:

AN:

1431630

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

707744

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32660

American (AMR)

AF:

0.00

AC:

AN:

42648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24728

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092174

Other (OTH)

AF:

0.000135

AC:

AN:

59076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41560

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00520

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.00260

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

May 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.15G>C (p.L5F) alteration is located in exon 2 (coding exon 1) of the ZBED4 gene. This alteration results from a G to C substitution at nucleotide position 15, causing the leucine (L) at amino acid position 5 to be replaced by a phenylalanine (F). 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

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

8.6

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.41

M_CAP

Benign

0.0059

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

0.30

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.080

REVEL

Benign

0.042

Sift

Benign

0.060

Sift4G

Benign

0.089

Polyphen

0.012

Vest4

0.033

MutPred

0.056

Gain of methylation at K6 (P = 0.0238);

MVP

0.068

MPC

0.49

ClinPred

0.19

GERP RS

0.30

Varity_R

0.023

gMVP

0.016

Mutation Taster

=100/0

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

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22-49883677-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over