rs386833956
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_004646.4(NPHS1):c.614_621delCACCCCGG(p.Thr205fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000254 in 1,613,568 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 frameshift
NM_004646.4 frameshift
Scores
Not classified
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.97
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 10 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;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NPHS1 | NM_004646.4 | c.614_621delCACCCCGG | p.Thr205fs | frameshift_variant | 6/29 | ENST00000378910.10 | NP_004637.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NPHS1 | ENST00000378910.10 | c.614_621delCACCCCGG | p.Thr205fs | frameshift_variant | 6/29 | 1 | NM_004646.4 | ENSP00000368190.4 | ||
| NPHS1 | ENST00000353632.6 | c.614_621delCACCCCGG | p.Thr205fs | frameshift_variant | 6/28 | 5 | ENSP00000343634.5 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251268Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135816
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461472Hom.: 0 AF XY: 0.0000261 AC XY: 19AN XY: 727084
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GnomAD4 genome 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74298
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ClinVar
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at