chr13-41065289-TAAA-T

Variant names:

• chr13-41065289-TAAA-T
• rs58699334
• NM_007187.5:c.262+21_262+23delAAA

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+5delAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,219,678 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 0.000073 (0 hom., cov: 25)
  • Exomes 𝑓: 0.027 (0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0781) population. However there is too low homozygotes in high coverage region: (expected more than 193, 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+21_262+23delAAA		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+5delAAA		splice_region intron	N/A	ENSP00000368801.3	O75554-1
	WBP4	ENST00000953016.1		c.262+3_262+5delAAA		splice_region intron	N/A	ENSP00000623075.1
	WBP4	ENST00000953017.1		c.199+3_199+5delAAA		splice_region intron	N/A	ENSP00000623076.1

Frequencies

GnomAD3 genomes AF: 0.0000734 AC: 6 AN: 81774 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: 0.000615

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000976

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0995 AC: 3401 AN: 34198 AF XY: 0.101

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.0940

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0988

Gnomad OTH exome AF: 0.0933

GnomAD4 exome AF: 0.0270 AC: 30698 AN: 1137876 Hom.: 0 AF XY: 0.0292 AC XY: 16218 AN XY: 554494

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

African (AFR) AF: 0.0385 AC: 933 AN: 24224

American (AMR) AF: 0.0818 AC: 1260 AN: 15396

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 959 AN: 16070

East Asian (EAS) AF: 0.0697 AC: 1964 AN: 28178

South Asian (SAS) AF: 0.0514 AC: 2598 AN: 50582

European-Finnish (FIN) AF: 0.0695 AC: 1668 AN: 23998

Middle Eastern (MID) AF: 0.0360 AC: 117 AN: 3250

European-Non Finnish (NFE) AF: 0.0209 AC: 19474 AN: 930276

Other (OTH) AF: 0.0376 AC: 1725 AN: 45902

⚠️ 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: 0.0000733 AC: 6 AN: 81802 Hom.: 0 Cov.: 25 AF XY: 0.0000784 AC XY: 3 AN XY: 38246

⚠️ 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: 21232

American (AMR) AF: 0.00 AC: 0 AN: 7076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2086

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2622

European-Finnish (FIN) AF: 0.000615 AC: 2 AN: 3250

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

European-Non Finnish (NFE) AF: 0.0000976 AC: 4 AN: 40990

Other (OTH) AF: 0.00 AC: 0 AN: 1092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000559552), 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		0.72
Mutation Taster		=100/0	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;