13-41068620-A-T

Variant names:

• chr13-41068620-A-T
• rs369882285
• NM_007187.5:c.322A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007187.5(WBP4):​c.322A>T​(p.Asn108Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N108D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WBP4 NM_007187.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.72
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27891028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007187.5. 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.322A>T	p.Asn108Tyr	missense	Exon 5 of 10	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.322A>T	p.Asn108Tyr	missense	Exon 5 of 10	ENSP00000368801.3	O75554-1
	WBP4	ENST00000953016.1		c.322A>T	p.Asn108Tyr	missense	Exon 5 of 10	ENSP00000623075.1
	WBP4	ENST00000953017.1		c.259A>T	p.Asn87Tyr	missense	Exon 4 of 9	ENSP00000623076.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461436 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.067
Sift	Uncertain	0.010	D
Polyphen		0.96	P
Vest4		0.33
MutPred		0.26		Gain of catalytic residue at P103 (P = 0.003)
MVP		0.58
MPC		0.086
ClinPred		0.89	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.19
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369882285; hg19: chr13-41642756;