19-35831678-AC-ACC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.3250dupG(p.Val1084GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). 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 |
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NPHS1 | ENST00000378910.10 | c.3250dupG | p.Val1084GlyfsTer12 | frameshift_variant | Exon 24 of 29 | 1 | NM_004646.4 | ENSP00000368190.4 | ||
NPHS1 | ENST00000353632.6 | c.3167-179dupG | intron_variant | Intron 23 of 27 | 5 | ENSP00000343634.5 |
Frequencies
GnomAD3 genomes AF: 0.0000398 AC: 6AN: 150662Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000760 AC: 18AN: 236910Hom.: 0 AF XY: 0.0000545 AC XY: 7AN XY: 128528
GnomAD4 exome AF: 0.000152 AC: 221AN: 1456162Hom.: 0 Cov.: 34 AF XY: 0.000170 AC XY: 123AN XY: 724184
GnomAD4 genome AF: 0.0000398 AC: 6AN: 150662Hom.: 0 Cov.: 31 AF XY: 0.0000408 AC XY: 3AN XY: 73494
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:13
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Variant summary: NPHS1 c.3250dupG (p.Val1084GlyfsX12) 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 0.00023 in 82306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.00023 vs 0.0034), allowing no conclusion about variant significance. c.3250dupG has been reported in the literature in multiple individuals affected with Nephrotic Syndrome, Type 1 (e.g. Heeringa 2008, Sadowski 2015). These data indicate that the variant is very likely to be associated with disease. 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome type 1 (MIM# 256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2 and v3: 25 heterozygotes, 0 homozygotes. (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in multiple unrelated individuals. This variant has been reported in multiple individuals with nephrotic syndrome (PMID: 35102923, 19194555, 22653594, 28392951, 25407002, ClinVar, LOVD). (SP) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Gly796Glu)) in a recessive disease. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The frameshift variant c.3250dup p.Val1084GlyfsTer12 in the NPHS1 gene has been reported previously in a heterozygous state in individuals affected with Congenital Nephrotic Syndrome and Steroid-Resistant Nephrotic Syndrome SRNS Bullich et al., 2015; Nguyen et al., 2017. This variant is reported with the allele frequency 0.007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Likely Pathogenic/ Pathogenic Multiple submissions. This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:4
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This sequence change creates a premature translational stop signal (p.Val1084Glyfs*12) 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 individuals with nephrotic syndrome (PMID: 9660941, 19194555, 23949594, 28392951). ClinVar contains an entry for this variant (Variation ID: 56497). 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. -
Identified with a second NPHS1 variant, either phase unknown or confirmed on the opposite allele (in trans) in multiple unrelated patients with congenital nephrotic syndrome referred for genetic testing at GeneDx and in the literature (PMID: 9660941, 23949594, 19194555); 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; This variant is associated with the following publications: (PMID: 23949594, 9660941, 19194555) -
Nephrotic syndrome Pathogenic:2
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This patient is also heterozygous for a known pathogenic variant, c.3250dup, in the NPHS1 gene. This frameshifting variant (dbSNP: rs386833936) is predicted to create a premature stop codon 11 positions downstream (p.Val1084Glyfs*12), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in patients with congenital nephrotic syndrome of Finnish type in the literature (Kestila et al 1998 Mol Cell 1:575-582; Lenkkeri et al 1999 Am J Hum Genet 64:51-61; Lee et al 2009 J Korean Med Sci 24:S210-S214). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at