13-41065289-TAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr13-41065289-TAA-T
• rs58699334
• NM_007187.5:c.262+22_262+23delAA

Variant summary

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

The ENST00000379487.5(WBP4):​c.262+3_262+4delAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0875 in 1,158,606 control chromosomes in the GnomAD database, including 6 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 0.0082 (5 hom., cov: 25)
  • Exomes 𝑓: 0.094 (1 hom.)
• Consequence: WBP4 ENST00000379487.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.724
• 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 = 0.00817 (668/81792) while in subpopulation AFR AF = 0.0291 (617/21218). AF 95% confidence interval is 0.0272. There are 5 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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+23delAA		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+3_262+4delAA		splice_region intron	N/A	ENSP00000368801.3	O75554-1
	WBP4	ENST00000953016.1		c.262+3_262+4delAA		splice_region intron	N/A	ENSP00000623075.1
	WBP4	ENST00000953017.1		c.199+3_199+4delAA		splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 666 AN: 81764 Hom.: 5 Cov.: 25

Gnomad AFR AF: 0.0291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00396

Gnomad ASJ AF: 0.000479

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000293

Gnomad OTH AF: 0.00276

GnomAD2 exomes AF: 0.148 AC: 5078 AN: 34198 AF XY: 0.148

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.161

GnomAD4 exome AF: 0.0936 AC: 100748 AN: 1076814 Hom.: 1 AF XY: 0.0965 AC XY: 50800 AN XY: 526334

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

African (AFR) AF: 0.118 AC: 2728 AN: 23162

American (AMR) AF: 0.156 AC: 2390 AN: 15330

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 2243 AN: 15726

East Asian (EAS) AF: 0.162 AC: 4564 AN: 28100

South Asian (SAS) AF: 0.128 AC: 6281 AN: 48940

European-Finnish (FIN) AF: 0.149 AC: 3578 AN: 23986

Middle Eastern (MID) AF: 0.132 AC: 413 AN: 3134

European-Non Finnish (NFE) AF: 0.0844 AC: 73817 AN: 874556

Other (OTH) AF: 0.108 AC: 4734 AN: 43880

⚠️ 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: 0.00817 AC: 668 AN: 81792 Hom.: 5 Cov.: 25 AF XY: 0.00805 AC XY: 308 AN XY: 38242

African (AFR) AF: 0.0291 AC: 617 AN: 21218

American (AMR) AF: 0.00396 AC: 28 AN: 7076

Ashkenazi Jewish (ASJ) AF: 0.000479 AC: 1 AN: 2088

East Asian (EAS) AF: 0.00 AC: 0 AN: 2816

South Asian (SAS) AF: 0.000381 AC: 1 AN: 2622

European-Finnish (FIN) AF: 0.00185 AC: 6 AN: 3250

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

European-Non Finnish (NFE) AF: 0.000293 AC: 12 AN: 40994

Other (OTH) AF: 0.00275 AC: 3 AN: 1090

Alfa AF: 0.00 Hom.: 98

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
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

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

Other links and lift over

dbSNP: rs58699334;

hg19: chr13-41639425;