chr19-35831678-AC-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):βc.3250delGβ(p.Val1084SerfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,606,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004646.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.3250delG | p.Val1084SerfsTer59 | frameshift_variant | Exon 24 of 29 | 1 | NM_004646.4 | ENSP00000368190.4 | ||
NPHS1 | ENST00000353632.6 | c.3167-179delG | intron_variant | Intron 23 of 27 | 5 | ENSP00000343634.5 |
Frequencies
GnomAD3 genomes AF: 0.0000332 AC: 5AN: 150662Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1456098Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 724130
GnomAD4 genome AF: 0.0000332 AC: 5AN: 150662Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2AN XY: 73494
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:8
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Variant summary: NPHS1 c.3250delG (p.Val1084SerfsX59) 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. The variant allele was found at a frequency of 5.5e-05 in 236910 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (5.5e-05 vs 0.0034), allowing no conclusion about variant significance. c.3250delG has been reported in the literature as a biallelic compound heterozygous genotype in individuals affected with congenital nephrotic syndrome of the Finnish type (Nephrotic Syndrome, Type 1). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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ACMG codes: PVS1; PS4M, PM2 -
not provided Pathogenic:2
This sequence change creates a premature translational stop signal (p.Val1084Serfs*59) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with NPHS1-related nephrotic syndrome (PMID: 10577936, 16518627). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56496). For these reasons, this variant has been classified as Pathogenic. -
Frameshift 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16518627, 31589614, 10577936) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at