rs267606916
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_153240.5(NPHP3):c.2104C>T(p.Arg702Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000961 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 0 hom. )
Consequence
NPHP3
NM_153240.5 stop_gained
NM_153240.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 4.40
Genes affected
NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
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 3-132696798-G-A is Pathogenic according to our data. Variant chr3-132696798-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132696798-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHP3 | NM_153240.5 | c.2104C>T | p.Arg702Ter | stop_gained | 15/27 | ENST00000337331.10 | |
NPHP3-ACAD11 | NR_037804.1 | n.2110C>T | non_coding_transcript_exon_variant | 14/45 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHP3 | ENST00000337331.10 | c.2104C>T | p.Arg702Ter | stop_gained | 15/27 | 1 | NM_153240.5 | P1 | |
NPHP3 | ENST00000490993.5 | n.1782C>T | non_coding_transcript_exon_variant | 11/23 | 5 | ||||
NPHP3 | ENST00000465756.5 | c.*79+462C>T | intron_variant, NMD_transcript_variant | 5 | |||||
NPHP3 | ENST00000684294.1 | c.*79+462C>T | intron_variant, NMD_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152156Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251404Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135874
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2022 | Observed with a pathogenic variant in a patient with a nephronophthisis-related ciliopathy in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Halbritter et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 19303681, 32040628, 23559409) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Nephronophthisis Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2640). This premature translational stop signal has been observed in individual(s) with nephronophthisis (PMID: 19303681). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs267606916, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Arg702*) in the NPHP3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHP3 are known to be pathogenic (PMID: 18371931, 23559409). - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
NPHP3-related Meckel-like syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 24, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Joubert syndrome and related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2022 | Variant summary: NPHP3 c.2104C>T (p.Arg702X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are associated with Nephronophthisis in HGMD. The variant allele was found at a frequency of 4.8e-05 in 251404 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NPHP3 causing Joubert Syndrome And Related Disorders (4.8e-05 vs 0.0004). c.2104C>T has been reported in the literature in individuals affected with Nephronophthisis and at-least one heterozygous individual with a diagnosis of Joubert Syndrome And Related Disorders (examples: Simpson_2009, Halbritter_2013, Iorio_2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Nephronophthisis 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2009 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
Vest4
GERP RS
Splicing
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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