rs386833921
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.2607_2608insCC(p.Asn870ProfsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,611,312 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. P869P) 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.2607_2608insCC | p.Asn870ProfsTer36 | frameshift_variant | 19/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.2607_2608insCC | p.Asn870ProfsTer36 | frameshift_variant | 19/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.2607_2608insCC | p.Asn870ProfsTer36 | frameshift_variant | 19/28 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000164 AC: 4AN: 243772Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131840
GnomAD4 exome AF: 0.0000322 AC: 47AN: 1459200Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21AN XY: 725654
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 19, 2020 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2021 | Variant summary: NPHS1 c.2606_2607dupCC (p.Asn870ProfsX36) 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 1.6e-05 in 243772 control chromosomes (gnomAD). The variant, c.2606_2607dupCC, has been reported in the literature in several compound heterozygous individuals affected with Nephrotic Syndrome, Type 1 (Lenkkeri_1999, Hinkes_2007, Machuca_2010, Wong_2013, Sadowski_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 15, 2023 | The NPHS1 c.2606_2607dup (p.Asn870ProfsTer36) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in four individuals with congenital nephrotic syndrome (CNS). In two individuals, the p.Asn870ProfsTer36 variant was identified in trans with a frameshift variant and a pathogenic missense (PMID: 17371932; 25349199). A second variant was not reported for the two other individuals. (PMID: 9915943; 20507940). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.2606_2607dup (p.Asn870ProfsTer36) variant is classified as pathogenic for congenital nephrotic syndrome. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Asn870Profs*36) 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). This variant is present in population databases (rs386833921, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 9915943, 19406966, 23949594). ClinVar contains an entry for this variant (Variation ID: 56482). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2023 | 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: 9915943, 23949594) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 01, 2020 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at