rs778217926
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.619del(p.Arg207GlyfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 frameshift
NM_004646.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.45
Genes affected
NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]
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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
Very rare variant in population databases, with high coverage;
PP5
Variant 19-35849642-CG-C is Pathogenic according to our data. Variant chr19-35849642-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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NPHS1 | NM_004646.4 | c.619del | p.Arg207GlyfsTer28 | frameshift_variant | 6/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.619del | p.Arg207GlyfsTer28 | frameshift_variant | 6/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.619del | p.Arg207GlyfsTer28 | frameshift_variant | 6/28 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251218Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135796
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461250Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 726968
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GnomAD4 genome AF: 0.0000394 AC: 6AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74314
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 06, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 11, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2021 | Variant summary: NPHS1 c.619delC (p.Arg207GlyfsX28) 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 8e-06 in 251218 control chromosomes. c.619delC has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1 (Machuca_2010, Wong_2013, Berody_2019). 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 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
NPHS1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 14, 2023 | The NPHS1 c.619delC variant is predicted to result in a frameshift and premature protein termination (p.Arg207Glyfs*28). This variant was reported in individuals with nephrotic syndrome (Machuca et al 2010. PubMed ID: 20507940; Bérody S et al 2019. PubMed ID: 29474669; Wong W et al 2013. PubMed ID: 23949594). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-36340544-CG-C). Frameshift variants in NPHS1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg207Glyfs*28) 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 (rs778217926, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with NPHS1-related conditions (PMID: 20507940, 29474669). ClinVar contains an entry for this variant (Variation ID: 370188). For these reasons, this variant has been classified as Pathogenic. - |
Nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | Jun 28, 2018 | This individual is heterozygous for the c.619del variant in the NPHS1 gene. This frameshifting variant is predicted to create a premature stop codon p.(Arg207Glyfs*28) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser (http://gnomad.broadinstitute.org) with a very low allele frequency of 0.008% (2 out of 246,004 alleles). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. However, other truncating variants downstream of this amino acid have been described in the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/?term=NPHS1%5Bgene%5D). This variant is considered to be likely pathogenic according to the ACMG guidelines. - |
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