Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001101669.3(INPP4B):c.2741C>G(p.Pro914Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P914H) has been classified as Uncertain significance.
INPP4B (HGNC:6075): (inositol polyphosphate-4-phosphatase type II B) INPP4B encodes the inositol polyphosphate 4-phosphatase type II, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. There is limited data to suggest that the human type II enzyme is subject to alternative splicing, as has been established for the type I enzyme. [provided by RefSeq, Jul 2008]
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33424
American (AMR)
AF:
0.00
AC:
0
AN:
44614
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26098
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39620
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86106
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111536
Other (OTH)
AF:
0.00
AC:
0
AN:
60354
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.