Genetic Variant WBP4:c.262+19_262+23delAAAAA (chr13-41065289-TAAAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000379487.5(WBP4):c.262+3_262+7delAAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,258,708 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000012 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0022 ( 0 hom. )

Consequence

WBP4
ENST00000379487.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.966

Publications

1 publications found

Variant links:

Genes affected

WBP4 (HGNC:12739): (WW domain binding protein 4) This gene encodes WW domain-containing binding protein 4. The WW domain represents a small and compact globular structure that interacts with proline-rich ligands. This encoded protein is a general spliceosomal protein that may play a role in cross-intron bridging of U1 and U2 snRNPs in the spliceosomal complex A. [provided by RefSeq, Jul 2008]

WBP4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities
Inheritance: AR Classification: MODERATE Submitted by: G2P

WBP4 links:

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new If you want to explore the variant's impact on the transcript ENST00000379487.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the AMR (0.00812) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379487.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WBP4	NM_007187.5	MANE Select	c.262+19_262+23delAAAAA		intron	N/A	NP_009118.1	O75554-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
WBP4	ENST00000379487.5	TSL:1 MANE Select	c.262+3_262+7delAAAAA	splice_region intron	N/A	ENSP00000368801.3	O75554-1
WBP4	ENST00000953016.1		c.262+3_262+7delAAAAA	splice_region intron	N/A	ENSP00000623075.1
WBP4	ENST00000953017.1		c.199+3_199+7delAAAAA	splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes

AF:

0.0000122

AC:

AN:

81792

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:

0.0000244

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00218

AC:

2568

AN:

1176916

Hom.:

AF XY:

0.00250

AC XY:

1436

AN XY:

573844

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00314

AC:

AN:

25196

American (AMR)

AF:

0.00935

AC:

149

AN:

15942

Ashkenazi Jewish (ASJ)

AF:

0.00536

AC:

AN:

16802

East Asian (EAS)

AF:

0.00527

AC:

157

AN:

29772

South Asian (SAS)

AF:

0.00401

AC:

211

AN:

52622

European-Finnish (FIN)

AF:

0.00611

AC:

152

AN:

24870

Middle Eastern (MID)

AF:

0.00179

AC:

AN:

3356

European-Non Finnish (NFE)

AF:

0.00163

AC:

1565

AN:

960758

Other (OTH)

AF:

0.00334

AC:

159

AN:

47598

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.264

Heterozygous variant carriers

274

548

822

1096

1370

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.0000122

AC:

AN:

81792

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

38222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21186

American (AMR)

AF:

0.00

AC:

AN:

7074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2088

East Asian (EAS)

AF:

0.00

AC:

AN:

2828

South Asian (SAS)

AF:

0.00

AC:

AN:

2628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.0000244

AC:

AN:

41004

Other (OTH)

AF:

0.00

AC:

AN:

1088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.97

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over