rs767018622
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_015272.5(RPGRIP1L):βc.2992delβ(p.Ile998PhefsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,594,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 6.9e-7 ( 0 hom. )
Consequence
RPGRIP1L
NM_015272.5 frameshift
NM_015272.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.156
Genes affected
RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-53638377-AT-A is Pathogenic according to our data. Variant chr16-53638377-AT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505092.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPGRIP1L | NM_015272.5 | c.2992del | p.Ile998PhefsTer5 | frameshift_variant | 20/27 | ENST00000647211.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPGRIP1L | ENST00000647211.2 | c.2992del | p.Ile998PhefsTer5 | frameshift_variant | 20/27 | NM_015272.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250706Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135518
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GnomAD4 exome AF: 6.93e-7 AC: 1AN: 1442910Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1AN XY: 719182
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152012Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74232
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Familial aplasia of the vermis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 06, 2016 | The p.Ile998PhefsX5 variant in RPGRIP1L has not been previously reported in the literature. It has been identified in 1/120,760 of chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org). This variant is predi cted to cause a frameshift, which alters the protein?s amino acid sequence begin ning at position 998 and leads to a premature termination codon 5 amino acids do wnstream. This alteration is then predicted to lead to a truncated or absent pro tein. Complete loss of RPGRIP1L function is an established disease mechanism in RPGRIP1L-related disorders such as Joubert syndrome and Meckel syndrome (Delous 2007). Moreover, Rpgrip1l -/- mice show a similar phenotype to individuals affec ted with these disorders including polydactyly, craniofacial malformations, and left-right symmetry defects (Vierkotten 2007). In summary, although additional studies are required to fully establish its clinical significance, the p.Ile998P hefsX5 variant is likely pathogenic. - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at