Genetic Variant WBP4:c.262+22_262+23dupAA (chr13-41065289-T-TAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000379487.5(WBP4):c.262+2_262+3insAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0223 in 1,202,544 control chromosomes in the GnomAD database, including 31 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 25)

Exomes 𝑓: 0.024 ( 30 hom. )

Consequence

WBP4
ENST00000379487.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0850

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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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 30 AR gene

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+22_262+23dupAA		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+2_262+3insAA	splice_region intron	N/A	ENSP00000368801.3	O75554-1
WBP4	ENST00000953016.1		c.262+2_262+3insAA	splice_region intron	N/A	ENSP00000623075.1
WBP4	ENST00000953017.1		c.199+2_199+3insAA	splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes

AF:

0.000330

AC:

AN:

81770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000141

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:

0.000366

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0239

AC:

26816

AN:

1120746

Hom.:

Cov.:

AF XY:

0.0236

AC XY:

12910

AN XY:

547936

show subpopulations

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

African (AFR)

AF:

0.0139

AC:

341

AN:

24570

American (AMR)

AF:

0.0137

AC:

219

AN:

15990

Ashkenazi Jewish (ASJ)

AF:

0.0120

AC:

199

AN:

16614

East Asian (EAS)

AF:

0.00930

AC:

276

AN:

29670

South Asian (SAS)

AF:

0.0147

AC:

770

AN:

52384

European-Finnish (FIN)

AF:

0.0212

AC:

523

AN:

24714

Middle Eastern (MID)

AF:

0.0118

AC:

AN:

3298

European-Non Finnish (NFE)

AF:

0.0258

AC:

23453

AN:

907650

Other (OTH)

AF:

0.0217

AC:

996

AN:

45856

⚠️ 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: 0.307

Heterozygous variant carriers

1998

3997

5995

7994

9992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

948

1896

2844

3792

4740

<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:

0.000330

AC:

AN:

81798

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

AN XY:

38246

show subpopulations

African (AFR)

AF:

0.000518

AC:

AN:

21232

American (AMR)

AF:

0.000141

AC:

AN:

7074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2086

East Asian (EAS)

AF:

0.00

AC:

AN:

2816

South Asian (SAS)

AF:

0.00

AC:

AN:

2622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

106

European-Non Finnish (NFE)

AF:

0.000366

AC:

AN:

40986

Other (OTH)

AF:

0.00

AC:

AN:

1092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.085

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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

Publications

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13-41065289-TAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over