rs386833998
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_015272.5(RPGRIP1L):c.723_726del(p.Asn241LysfsTer25) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000616 in 1,461,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
RPGRIP1L
NM_015272.5 frameshift
NM_015272.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.24
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 16-53686482-TTTCA-T is Pathogenic according to our data. Variant chr16-53686482-TTTCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 56562.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-53686482-TTTCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPGRIP1L | NM_015272.5 | c.723_726del | p.Asn241LysfsTer25 | frameshift_variant | 6/27 | ENST00000647211.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPGRIP1L | ENST00000647211.2 | c.723_726del | p.Asn241LysfsTer25 | frameshift_variant | 6/27 | NM_015272.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461392Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 726990
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
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 05, 2022 | This sequence change creates a premature translational stop signal (p.Asn241Lysfs*25) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56562). This variant is also known as c.721_4delAATG (p.N241fsX25). This premature translational stop signal has been observed in individual(s) with RPGRIP1L-related conditions (PMID: 21068128). This variant is not present in population databases (gnomAD no frequency). - |
Meckel syndrome, type 5 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at