Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_001377142.1(PLCB4):c.1898G>T(p.Arg633Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).
PLCB4 (HGNC:9059): (phospholipase C beta 4) The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate. This reaction uses calcium as a cofactor and plays an important role in the intracellular transduction of many extracellular signals in the retina. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2010]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the PLCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 18 curated benign missense variants. Gene score misZ: 3.5718 (above the threshold of 3.09). Trascript score misZ: 3.2758 (above the threshold of 3.09). GenCC associations: The gene is linked to auriculocondylar syndrome 1, auriculocondylar syndrome, auriculocondylar syndrome 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 20-9409080-G-T is Pathogenic according to our data. Variant chr20-9409080-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 64692.Status of the report is no_assertion_criteria_provided, 0 stars.