rs370210428
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong
The NM_015102.5(NPHP4):c.133C>T(p.Gln45Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.0000892 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_015102.5 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHP4 | NM_015102.5 | c.133C>T | p.Gln45Ter | stop_gained, splice_region_variant | 2/30 | ENST00000378156.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHP4 | ENST00000378156.9 | c.133C>T | p.Gln45Ter | stop_gained, splice_region_variant | 2/30 | 1 | NM_015102.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000321 AC: 8AN: 248934Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135120
GnomAD4 exome AF: 0.0000951 AC: 139AN: 1461494Hom.: 0 Cov.: 31 AF XY: 0.000103 AC XY: 75AN XY: 727004
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 08, 2023 | Reported as a heterozygous variant in unrelated patients with nephropathy or end stage renal disease in published literature; however, a second variant in NPHP4 was not reported (Halbritter et al., 2013; Groopman et al., 2019); 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; This variant is associated with the following publications: (PMID: 31964843, 23559409, 34216551, 30586318) - |
Senior-Loken syndrome 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center | Nov 05, 2020 | The c.133C>T variant in the NPHP4 gene is a heterozygous nonsense variant, which results in a premature stop codon at the position 45 (p.Gln45Ter). This premature truncation occurs in coding exon 2 of the NPHP4 gene (30 exons total; NM_015102.5). Loss-of-function variants in NPHP4 have been established to be pathogenic (PMIDs: 12205563, 23559409). Several different loss-of-function variants distal to this one have been described to be disease causing. This variant has been observed in the Genome Aggregation Database (gnomAD) at a very low frequency (allele frequency = 0.00003210, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported in the heterozygous state in an individual with nephronophthisis-related ciliopathy (PMID: 23559409). - |
Nephronophthisis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 562355). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with a nephronophthisis-related ciliopathy (PMID: 23559409). This variant is present in population databases (rs370210428, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Gln45*) in the NPHP4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHP4 are known to be pathogenic (PMID: 12205563, 23559409). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at