Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_015874.6(RBPJ):c.154A>G(p.Arg52Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52T) has been classified as Likely pathogenic.
RBPJ (HGNC:5724): (recombination signal binding protein for immunoglobulin kappa J region) The protein encoded by this gene is a transcriptional regulator important in the Notch signaling pathway. The encoded protein acts as a repressor when not bound to Notch proteins and an activator when bound to Notch proteins. It is thought to function by recruiting chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins to Notch signaling pathway genes. Several transcript variants encoding different isoforms have been found for this gene, and several pseudogenes of this gene exist on chromosome 9. [provided by RefSeq, Oct 2013]
Verdict is Pathogenic. Variant got 17 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a strand (size 7) in uniprot entity SUH_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_015874.6
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr4-26406270-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1803755.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, RBPJ
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-26406269-A-G is Pathogenic according to our data. Variant chr4-26406269-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
.;.;.;Gain of ubiquitination at K64 (P = 0.0358);.;Gain of ubiquitination at K64 (P = 0.0358);Gain of ubiquitination at K64 (P = 0.0358);.;.;.;.;.;.;.;.;.;.;.;