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rs386833906

chr19-35844141-TCA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_004646.4(NPHS1):c.2172_2173del(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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.04
Variant links:
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
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
NPHS1NM_004646.4 linkuse as main transcriptc.2172_2173del p.Glu725GlyfsTer25 frameshift_variant 16/29 ENST00000378910.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHS1ENST00000378910.10 linkuse as main transcriptc.2172_2173del p.Glu725GlyfsTer25 frameshift_variant 16/291 NM_004646.4 P2O60500-1
NPHS1ENST00000585400.1 linkuse as main transcriptn.354_355del non_coding_transcript_exon_variant 3/31
NPHS1ENST00000353632.6 linkuse as main transcriptc.2172_2173del p.Glu725GlyfsTer25 frameshift_variant 16/285 A2O60500-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000405
AC:
1
AN:
247024
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134372
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1457290
Hom.:
0
AF XY:
0.00000276
AC XY:
2
AN XY:
725162
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
32
Bravo
AF:
0.00000378

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, no assertion criteria providedresearchDepartment of Traditional Chinese Medicine, Fujian Provincial Hospital-- -
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 08, 2022- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeFeb 25, 2021For 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.23
Position offset: -38

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833906; hg19: chr19-36335043; API