chr19-35831056-G-A

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

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24

Conservation

PhyloP100: 0.829
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]

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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS1NM_004646.4 linkc.3478C>T p.Arg1160* stop_gained Exon 27 of 29 ENST00000378910.10 NP_004637.1 O60500-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHS1ENST00000378910.10 linkc.3478C>T p.Arg1160* stop_gained Exon 27 of 29 1 NM_004646.4 ENSP00000368190.4 O60500-1
NPHS1ENST00000353632.6 linkc.3358C>T p.Arg1120* stop_gained Exon 26 of 28 5 ENSP00000343634.5 O60500-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000994
AC:
25
AN:
251434
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135902
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000602
AC:
88
AN:
1461784
Hom.:
0
Cov.:
33
AF XY:
0.0000688
AC XY:
50
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000441
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152130
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000780
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

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
Jun 25, 2017
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Previously reported pathogenic nonsense variant reported in 16 patients (PMID: 11854170) with additional cases reported in literature. -

Dec 01, 2023
Precision Medicine Center, Zhengzhou University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1,PM2_p,PM3,PP4 -

May 20, 2023
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

May 22, 2022
3billion, Medical Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 02, 2014
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 10, 2021
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -

-
Centogene AG - the Rare Disease Company
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 15, 2002
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Mar 23, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 24, 2024
Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Apr 17, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:6
Dec 30, 2019
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Mar 19, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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) -

Jul 13, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Nephrotic syndrome Pathogenic:2
May 10, 2019
Sydney Genome Diagnostics, Children's Hospital Westmead
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

Nov 10, 2017
Yale Center for Mendelian Genomics, Yale University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1
Dec 06, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.25
Eigen_PC
Benign
-0.083
FATHMM_MKL
Benign
0.049
N
Vest4
0.68
GERP RS
3.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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: rs267606919; hg19: chr19-36321958; API