13-41065289-TAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant names:

• chr13-41065289-T-TA
• rs58699334
• NM_007187.5:c.262+23dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000379487.5(WBP4):​c.262+2_262+3insA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 1,243,866 control chromosomes in the GnomAD database, including 59 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (23 hom., cov: 25)
  • Exomes 𝑓: 0.020 (36 hom.)
• Consequence: WBP4 ENST00000379487.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• Publications: 1 publications found

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

ACMG classification

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

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0148 (1212/81698) while in subpopulation AFR AF = 0.0353 (748/21198). AF 95% confidence interval is 0.0332. There are 23 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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+23dupA		intron	N/A	NP_009118.1	O75554-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WBP4	ENST00000379487.5	TSL:1 MANE Select	c.262+2_262+3insA		splice_region intron	N/A	ENSP00000368801.3	O75554-1
	WBP4	ENST00000953016.1		c.262+2_262+3insA		splice_region intron	N/A	ENSP00000623075.1
	WBP4	ENST00000953017.1		c.199+2_199+3insA		splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 1211 AN: 81670 Hom.: 23 Cov.: 25

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.0171

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00283

Gnomad SAS AF: 0.00534

Gnomad FIN AF: 0.00277

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0189 AC: 645 AN: 34198 AF XY: 0.0173

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0211

Gnomad FIN exome AF: 0.00789

Gnomad NFE exome AF: 0.0185

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0201 AC: 23382 AN: 1162168 Hom.: 36 Cov.: 0 AF XY: 0.0203 AC XY: 11512 AN XY: 567016

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

African (AFR) AF: 0.0194 AC: 485 AN: 25034

American (AMR) AF: 0.0220 AC: 352 AN: 16030

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 251 AN: 16824

East Asian (EAS) AF: 0.0130 AC: 389 AN: 29902

South Asian (SAS) AF: 0.0208 AC: 1100 AN: 52780

European-Finnish (FIN) AF: 0.0254 AC: 634 AN: 24952

Middle Eastern (MID) AF: 0.0155 AC: 52 AN: 3360

European-Non Finnish (NFE) AF: 0.0202 AC: 19140 AN: 946120

Other (OTH) AF: 0.0208 AC: 979 AN: 47166

⚠️ 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.

GnomAD4 genome AF: 0.0148 AC: 1212 AN: 81698 Hom.: 23 Cov.: 25 AF XY: 0.0151 AC XY: 576 AN XY: 38206

African (AFR) AF: 0.0353 AC: 748 AN: 21198

American (AMR) AF: 0.0252 AC: 178 AN: 7074

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 3 AN: 2088

East Asian (EAS) AF: 0.00284 AC: 8 AN: 2812

South Asian (SAS) AF: 0.00535 AC: 14 AN: 2618

European-Finnish (FIN) AF: 0.00277 AC: 9 AN: 3252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 106

European-Non Finnish (NFE) AF: 0.00559 AC: 229 AN: 40932

Other (OTH) AF: 0.0128 AC: 14 AN: 1092

Alfa AF: 0.00 Hom.: 98

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.085
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs58699334; hg19: chr13-41639425;