dbSNP rs910799: ZBED4:p.Ile420Val (chr22-49884920-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014838.3(ZBED4):c.1258A>G(p.Ile420Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.773 in 1,605,264 control chromosomes in the GnomAD database, including 491,664 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.65 ( 36656 hom., cov: 34)

Exomes 𝑓: 0.79 ( 455008 hom. )

Consequence

ZBED4
NM_014838.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

43 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.5252267E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBED4	NM_014838.3 link	c.1258A>G	p.Ile420Val	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.1258A>G	p.Ile420Val	missense_variant	Exon 2 of 2	1	NM_014838.3	ENSP00000216268.4	O75132
ZBED4	ENST00000850559.1 link	c.1258A>G	p.Ile420Val	missense_variant	Exon 2 of 2			ENSP00000520851.1
ZBED4	ENST00000850560.1 link	n.260+1442A>G		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes

AF:

0.654

AC:

99413

AN:

152108

Hom.:

36655

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.533

Gnomad AMR

AF:

0.784

Gnomad ASJ

AF:

0.754

Gnomad EAS

AF:

0.856

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.842

Gnomad MID

AF:

0.707

Gnomad NFE

AF:

0.803

Gnomad OTH

AF:

0.703

GnomAD2 exomes

AF:

0.761

AC:

186306

AN:

244900

AF XY:

0.761

show subpopulations

Gnomad AFR exome

AF:

0.264

Gnomad AMR exome

AF:

0.854

Gnomad ASJ exome

AF:

0.745

Gnomad EAS exome

AF:

0.868

Gnomad FIN exome

AF:

0.846

Gnomad NFE exome

AF:

0.804

Gnomad OTH exome

AF:

0.780

GnomAD4 exome

AF:

0.786

AC:

1141378

AN:

1453038

Hom.:

455008

Cov.:

AF XY:

0.782

AC XY:

564471

AN XY:

722026

show subpopulations

African (AFR)

AF:

0.253

AC:

8450

AN:

33342

American (AMR)

AF:

0.846

AC:

37226

AN:

43982

Ashkenazi Jewish (ASJ)

AF:

0.755

AC:

19264

AN:

25528

East Asian (EAS)

AF:

0.863

AC:

34191

AN:

39610

South Asian (SAS)

AF:

0.641

AC:

54606

AN:

85244

European-Finnish (FIN)

AF:

0.842

AC:

44564

AN:

52908

Middle Eastern (MID)

AF:

0.685

AC:

3912

AN:

5710

European-Non Finnish (NFE)

AF:

0.807

AC:

893573

AN:

1106748

Other (OTH)

AF:

0.760

AC:

45592

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

15362

30724

46087

61449

76811

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20688

41376

62064

82752

103440

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.653

AC:

99415

AN:

152226

Hom.:

36656

Cov.:

AF XY:

0.659

AC XY:

49038

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.277

AC:

11488

AN:

41524

American (AMR)

AF:

0.785

AC:

11996

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.754

AC:

2618

AN:

3470

East Asian (EAS)

AF:

0.856

AC:

4425

AN:

5168

South Asian (SAS)

AF:

0.657

AC:

3168

AN:

4824

European-Finnish (FIN)

AF:

0.842

AC:

8944

AN:

10620

Middle Eastern (MID)

AF:

0.723

AC:

211

AN:

292

European-Non Finnish (NFE)

AF:

0.803

AC:

54606

AN:

68018

Other (OTH)

AF:

0.699

AC:

1474

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1387

2774

4161

5548

6935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

768

1536

2304

3072

3840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.758

Hom.:

142245

Bravo

AF:

0.639

TwinsUK

AF:

0.806

AC:

2987

ALSPAC

AF:

0.807

AC:

3112

ESP6500AA

AF:

0.293

AC:

1292

ESP6500EA

AF:

0.797

AC:

6858

ExAC

AF:

0.748

AC:

90722

Asia WGS

AF:

0.701

AC:

2438

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.10

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.021

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.12

MetaRNN

Benign

9.5e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.095

PhyloP100

1.4

PrimateAI

Benign

0.38

PROVEAN

Benign

0.070

REVEL

Benign

0.029

Sift

Benign

1.0

Sift4G

Benign

0.62

Polyphen

0.0

Vest4

0.0090

MPC

0.35

ClinPred

0.0065

GERP RS

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.019

gMVP

0.12

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over