Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_015874.6(RBPJ):āc.154A>Gā(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 (ā ā ). 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
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
Very rare variant in population databases, with high coverage;
PM5
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
Missense variant where missense usually causes diseases, RBPJ
PP3
MetaRNN computational evidence supports a deleterious effect, 0.937
PP5
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.
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