rs150855173
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.3442C>T(p.Gln1148Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000409 in 1,613,990 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1148Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004646.4 stop_gained
Scores
Clinical Significance
Conservation
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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.3442C>T | p.Gln1148Ter | stop_gained | 27/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.3442C>T | p.Gln1148Ter | stop_gained | 27/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.3322C>T | p.Gln1108Ter | stop_gained | 26/28 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251274Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135854
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461830Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 727220
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Nov 26, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 11, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2018 | Variant summary: NPHS1 c.3442C>T (p.Gln1148X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position have been classified as pathogenic by our laboratory (c.3478C>T (p.Arg1160X)). The variant allele was found at a frequency of 8.1e-06 in 246066 control chromosomes (gnomAD). c.3442C>T has been reported in the literature in multiple compound heterozygous individuals affected with congenital Nephrotic Syndrome, Type 1 (Beltcheva 2001, Schoeb 2010, Wong 2013, Bierzynska 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. 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 12, 2023 | This sequence change creates a premature translational stop signal (p.Gln1148*) 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 (rs150855173, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with nephrotic syndrome (PMID: 23949594, 24902943). ClinVar contains an entry for this variant (Variation ID: 189074). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at