rs386833906
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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):βc.2172_2173delβ(p.Glu725GlyfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 frameshift
NM_004646.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.04
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 19-35844141-TCA-T is Pathogenic according to our data. Variant chr19-35844141-TCA-T is described in ClinVar as [Pathogenic]. Clinvar id is 56466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35844141-TCA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.2172_2173del | p.Glu725GlyfsTer25 | frameshift_variant | 16/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.2172_2173del | p.Glu725GlyfsTer25 | frameshift_variant | 16/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000585400.1 | n.354_355del | non_coding_transcript_exon_variant | 3/3 | 1 | ||||
NPHS1 | ENST00000353632.6 | c.2172_2173del | p.Glu725GlyfsTer25 | frameshift_variant | 16/28 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247024Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134372
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457290Hom.: 0 AF XY: 0.00000276 AC XY: 2AN XY: 725162
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 08, 2022 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, no assertion criteria provided | research | Department of Traditional Chinese Medicine, Fujian Provincial Hospital | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 25, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with nephrotic syndrome (PMID: 16703378). ClinVar contains an entry for this variant (Variation ID: 56466). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu725Glyfs*25) 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). - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -38
Find out detailed SpliceAI scores and Pangolin per-transcript scores at