chr19-35831056-G-A
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.3478C>T(p.Arg1160*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 stop_gained
NM_004646.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.829
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]
Genome browser will be placed here
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 19-35831056-G-A is Pathogenic according to our data. Variant chr19-35831056-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831056-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 31
GnomAD3 genomes
AF:
AC:
1
AN:
152130
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000994 AC: 25AN: 251434Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135902
GnomAD3 exomes
AF:
AC:
25
AN:
251434
Hom.:
AF XY:
AC XY:
17
AN XY:
135902
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461784Hom.: 0 Cov.: 33 AF XY: 0.0000688 AC XY: 50AN XY: 727202
GnomAD4 exome
AF:
AC:
88
AN:
1461784
Hom.:
Cov.:
33
AF XY:
AC XY:
50
AN XY:
727202
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.00000657 AC: 1AN: 152130Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74322
GnomAD4 genome
AF:
AC:
1
AN:
152130
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
74322
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
AF:
AC:
8
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:24
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:15
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006873 / PMID: 9915943). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | clinical testing | Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences | Apr 24, 2024 | A heterozygous nonsense variant c.3478C>T in exon 27 of NPHS1 gene (chr19:36321958; Depth: 41x) was detected. This individual is heterozygous for a pathogenic variant, c.3478C>T, in the NPHS1 gene. This variant creates a premature stop codon p.(Arg1160*) and may result in a null allele due to nonsense-mediated mRNA decay. This variant has been reported in the gnomAD browser with a very low allele frequency of 0.01%. This variant is considered to be pathogenic according to the ACMG guidelines. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 10, 2021 | The NPHS1 c.3478C>T (p.Arg1160Ter) variant is a stop-gained variant that is predicted to result in an absent or truncated protein product. Across a selection of the available literature, this variant has been identified in a homozygous state in 25 individuals with congenital nephrotic syndrome and in a presumed homozygous state in four additional cases (Koziell et al. 2002; Ovunc et al. 2012; Lenkkeri et al. 2013; Lovric et al. 2014; Cil et al. 2015; Amr et al. 2020; Wong et al. 2021). It has been proposed as a founder variant in Malta and has also been reported in a presumed compound heterozygous state with another stop-gained variant in one individual and in a confirmed compound heterozygous state with the p.Tyr977Cys variant in four affected siblings (Ovunc et al. 2012; Wang et al. 2017). Some individuals with this variant presented with slow disease progression. The p.Arg1160Ter variant is reported at a frequency of 0.000392 in the South Asian population of the Genome Aggregation Database (version 2.1.1). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber et al. 2003). Based on the collective evidence, the p.Arg1160Ter variant is classified as pathogenic for congenital nephrotic syndrome. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 17, 2017 | Variant summary: The NPHS1 c.3478C>T (p.Arg1160X) variant results in a premature termination codon, predicted to cause a truncated or absent NPHS1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Nonsense mutations nearby to this variant have been classified as pathogenic by our laboratory previously (e.g., c.3325C>T [p.Arg1109X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and in control cohorts in the literature at a frequency of 0.000074 (9/121544 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). Numerous publications have found the variant among patient cohorts as a homozygous genotype. In particular, the variant appears to be a founder mutation in Maltese individuals, where a study showed that of 50 non-Finnish patients analyzed, 12 were homozygous for the variant, 9 of which were from Malta (Koziell_HMG_2002). Additionally, a functional study showed that the variant prevents recruitment of nephrin (the protein product of NPHS1) into the lipid raft at the plasma membrane, which is important for many cellular processes, such as polarized sorting of membrane proteins and signal transduction (Huber_HMG_2003). In addition, one reputable database has classified this variant as pathogenic, though the last evaluation was in 2002. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Precision Medicine Center, Zhengzhou University | Dec 01, 2023 | PVS1,PM2_p,PM3,PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | May 20, 2023 | The observed stop gained c.3478C>T(p.Arg1160Ter) variant in NPHS1 gene has been reported in homozygous or compound heterozygous state in individual(s) affected with nephrotic syndrome (Koziell A, et. al., 2002; Cil O, et. al., 2015; Wang F, et. al.,2017). Functional studies conducted in HEK293 cells showed that the truncated protein resulting from this variant does not interact with podocin and failed to be recruited by podocin into lipid rafts at the plasma membrane (Huber TB, et. al., 2003). This variant is present with an allele frequency of 0.01% in gnomAD Exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - disease causing) predicts conflicting evidence on protein structure and function for this variant. The nucleotide change c.3478C>T in NPHS1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 02, 2014 | - - |
| Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jun 25, 2017 | Previously reported pathogenic nonsense variant reported in 16 patients (PMID: 11854170) with additional cases reported in literature. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 15, 2002 | - - |
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg1160*) 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 (rs267606919, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 16518627, 24742477, 24902943, 25720465, 28204945). ClinVar contains an entry for this variant (Variation ID: 6873). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jul 13, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 30, 2019 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2024 | Nonsense 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; This variant is associated with the following publications: (PMID: 32779909, 34859019, 24742477, 24498843, 25525159, 28204945, 16518627, 31456999, 32363171, 34426522, 33565430, 31589614, 32860008, 32604935, 35064937, 36245711, 9915943, 29127259, 33980730, 37204080, 35755072) - |
Nephrotic syndrome Pathogenic:2
| Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Nov 10, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sydney Genome Diagnostics, Children's Hospital Westmead | May 10, 2019 | This individual is heterozygous for a pathogenic variant, c.3478C>T, in the NPHS1 gene. This variant creates a premature stop codon p.(Arg1160*) 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 0.01% (25 out of 246,216 alleles). The c.3478C>T p.(Arg1160*) variant has been reported in several patients from India and Malta origin with the mild congenital nephrotic syndrome of Finnish type (CNF, Koziell et al 2002 Hum Mol Genet 11: 379-388; Heeringa et al 2008 Nephrol Dial Translplant 23: 3527-3533; Machuca et al 2010 J Am Soc Nephrol 21: 1209-1217; Wang et al 2016; HK J Paediatr 21: 294-297). This variant is considered to be pathogenic according to the ACMG guidelines (Evidence used: PVS1, PM2, PM3). - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2024 | The c.3478C>T (p.R1160*) alteration, located in exon 27 (coding exon 27) of the NPHS1 gene, consists of a C to T substitution at nucleotide position 3478. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 1160. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.01% (25/251434) total alleles studied. The highest observed frequency was 0.039% (12/30616) of South Asian alleles. This variant has been identified in the homozygous state and in conjunction with other NPHS1 variants in individuals with features consistent with NPHS1-related nephrotic syndrome; in at least one instance, the variants were identified in trans (Al Riyami, 2023; Elshafey, 2023; Lu, 2022; Zhu, 2022; Espinosa, 2022; Liu, 2022; Joshi, 2021; Rong, 2021; Warejko, 2018; Bierzynska, 2017; Lenkkeri, 1999). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at