rs386833864
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004646.4(NPHS1):āc.1096A>Cā(p.Ser366Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,878 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S366N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004646.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.1096A>C | p.Ser366Arg | missense_variant | 9/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.1096A>C | p.Ser366Arg | missense_variant | 9/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.1096A>C | p.Ser366Arg | missense_variant | 9/28 | 5 | A2 | ||
NPHS1 | ENST00000592132.1 | n.103A>C | non_coding_transcript_exon_variant | 2/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 152156Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251380Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727238
GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:6
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 26, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4_MOD,PM2,PP2,PP3,PP4. - |
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 27, 2023 | Variant summary: NPHS1 c.1096A>C (p.Ser366Arg) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1096A>C has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g., Lenkkeri_1999, Machuca_2010). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant disrupts protein localization and folding leading to retention and eventual degradation in the endoplasmic reticulum (e.g., Liu_2001, Drozova_2013, Yoshida_2021). Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 15, 2023 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 366 of the NPHS1 protein (p.Ser366Arg). This variant is present in population databases (rs386833864, gnomAD 0.0009%). This missense change has been observed in individuals with NPHS1-related conditions (PMID: 9915943, 18709391, 20172850, 24371179, 24397250). ClinVar contains an entry for this variant (Variation ID: 56420). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPHS1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NPHS1 function (PMID: 11726550, 18614772, 24303155). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at