rs755254230
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The ENST00000378910.10(NPHS1):āc.1714A>Gā(p.Ser572Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,732 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S572N) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000378910.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.1714A>G | p.Ser572Gly | missense_variant | 13/29 | ENST00000378910.10 | NP_004637.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.1714A>G | p.Ser572Gly | missense_variant | 13/29 | 1 | NM_004646.4 | ENSP00000368190 | P2 | |
NPHS1 | ENST00000353632.6 | c.1714A>G | p.Ser572Gly | missense_variant | 13/28 | 5 | ENSP00000343634 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 250578Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135608
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461732Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4AN XY: 727174
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 09, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser572 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15906409, 20172850, 29474669). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. ClinVar contains an entry for this variant (Variation ID: 550087). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 26248470). This variant is present in population databases (rs755254230, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 572 of the NPHS1 protein (p.Ser572Gly). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 28, 2021 | Variant summary: NPHS1 c.1714A>G (p.Ser572Gly) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250578 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1714A>G has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with focal segmental glomerulosclerosis in whom segregation analysis to determine variant phase was not performed (FSGS) (example, Weber_2014). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at