chr19-35830889-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.3549C>A(p.Tyr1183Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,776 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. Y1183Y) has been classified as Likely benign.
Frequency
Consequence
NM_004646.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.3549C>A | p.Tyr1183Ter | stop_gained | 28/29 | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.3549C>A | p.Tyr1183Ter | stop_gained | 28/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.3429C>A | p.Tyr1143Ter | stop_gained | 27/28 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461588Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727138
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74348
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 11, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 22, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 04, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 15, 2022 | Variant summary: NPHS1 c.3549C>A (p.Tyr1183X) 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. Truncations downstream of this position have been in affected individuals (HGMD). The variant was absent in 251472 control chromosomes (gnomAD). To our knowledge, no occurrence of c.3549C>A in individuals affected with Nephrotic Syndrome, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Kidney disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 01, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Tyr1183*) 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 (no rsID available, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NPHS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 552390). 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