rs386833883
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.1481del(p.Ser494CysfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,596,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S494S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004646.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.1481del | p.Ser494CysfsTer55 | frameshift_variant | 12/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.1481del | p.Ser494CysfsTer55 | frameshift_variant | 12/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.1481del | p.Ser494CysfsTer55 | frameshift_variant | 12/28 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000471 AC: 1AN: 212490Hom.: 0 AF XY: 0.00000859 AC XY: 1AN XY: 116428
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1444086Hom.: 0 Cov.: 37 AF XY: 0.00000139 AC XY: 1AN XY: 717006
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2021 | Variant summary: NPHS1 c.1481delC (p.Ser494CysfsX55) 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 have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.7e-06 in 212490 control chromosomes. c.1481delC has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (e.g. Bolk_1999). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1999 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 09, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 17, 2023 | ClinVar contains an entry for this variant (Variation ID: 56441). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 10577936, 18614772). This variant is present in population databases (rs386833883, gnomAD 0.001%). This sequence change creates a premature translational stop signal (p.Ser494Cysfs*55) in the NPHS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHS1 are known to be pathogenic (PMID: 11317351, 11854170, 12039988). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2022 | Frameshift 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: 31028937, 10577936, 18614772) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at