rs778824093
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015272.5(RPGRIP1L):βc.2794_2795delβ(p.Leu932ArgfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000026 ( 0 hom., cov: 32)
Exomes π: 0.0000089 ( 0 hom. )
Consequence
RPGRIP1L
NM_015272.5 frameshift
NM_015272.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.23
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 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 16-53641363-TAA-T is Pathogenic according to our data. Variant chr16-53641363-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 406251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPGRIP1L | NM_015272.5 | c.2794_2795del | p.Leu932ArgfsTer22 | frameshift_variant | 18/27 | ENST00000647211.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPGRIP1L | ENST00000647211.2 | c.2794_2795del | p.Leu932ArgfsTer22 | frameshift_variant | 18/27 | NM_015272.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251132Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135712
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461790Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727190
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 406251). This sequence change creates a premature translational stop signal (p.Leu932Argfs*22) in the RPGRIP1L gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPGRIP1L are known to be pathogenic (PMID: 17558409). This variant is present in population databases (rs778824093, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RPGRIP1L-related conditions. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2021 | The c.2794_2795delTT (p.L932Rfs*22) alteration, located in exon 18 (coding exon 17) of the RPGRIP1L gene, consists of a deletion of 2 nucleotides from position 2794 to 2795, causing a translational frameshift with a predicted alternate stop codon after 22 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been previously identified in the compound heterozygous state with a second RPGRIP1L variant, confirmed in trans by parental testing, in a patient with ciliopathy (Pajusalu, 2018). Based on the available evidence, this alteration is classified as 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