13-41065289-TAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr13-41065289-TAAAA-T
• rs58699334
• NM_007187.5:c.262+20_262+23delAAAA

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+6delAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,248,114 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000049 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0080 (0 hom.)
• Consequence: WBP4 ENST00000379487.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.966
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0271) population. However there is too low homozygotes in high coverage region: (expected more than 17, 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+20_262+23delAAAA		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+6delAAAA		splice_region intron	N/A	ENSP00000368801.3	O75554-1
	WBP4	ENST00000953016.1		c.262+3_262+6delAAAA		splice_region intron	N/A	ENSP00000623075.1
	WBP4	ENST00000953017.1		c.199+3_199+6delAAAA		splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes AF: 0.0000489 AC: 4 AN: 81788 Hom.: 0 Cov.: 25

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: 0.0000976

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0375 AC: 1281 AN: 34198 AF XY: 0.0384

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.0380

Gnomad FIN exome AF: 0.0383

Gnomad NFE exome AF: 0.0369

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.00796 AC: 9281 AN: 1166326 Hom.: 0 AF XY: 0.00877 AC XY: 4985 AN XY: 568302

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

African (AFR) AF: 0.0124 AC: 309 AN: 24864

American (AMR) AF: 0.0293 AC: 457 AN: 15604

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 278 AN: 16470

East Asian (EAS) AF: 0.0214 AC: 623 AN: 29122

South Asian (SAS) AF: 0.0169 AC: 875 AN: 51806

European-Finnish (FIN) AF: 0.0220 AC: 537 AN: 24430

Middle Eastern (MID) AF: 0.0163 AC: 54 AN: 3306

European-Non Finnish (NFE) AF: 0.00589 AC: 5616 AN: 953620

Other (OTH) AF: 0.0113 AC: 532 AN: 47104

⚠️ 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: 0.0000489 AC: 4 AN: 81788 Hom.: 0 Cov.: 25 AF XY: 0.0000262 AC XY: 1 AN XY: 38220

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

African (AFR) AF: 0.00 AC: 0 AN: 21186

American (AMR) AF: 0.00 AC: 0 AN: 7074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2088

East Asian (EAS) AF: 0.00 AC: 0 AN: 2828

South Asian (SAS) AF: 0.00 AC: 0 AN: 2628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 112

European-Non Finnish (NFE) AF: 0.0000976 AC: 4 AN: 41002

Other (OTH) AF: 0.00 AC: 0 AN: 1088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000294109), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 98

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
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;