rs386833914
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.248_249insA(p.Tyr83Ter) variant causes a stop gained, frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y83Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004646.4 stop_gained, frameshift
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.248_249insA | p.Tyr83Ter | stop_gained, frameshift_variant | 2/29 | ENST00000378910.10 | |
KIRREL2 | XM_011527362.2 | c.-424dup | 5_prime_UTR_variant | 1/16 | |||
KIRREL2 | XM_011527363.2 | c.-415dup | 5_prime_UTR_variant | 1/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.248_249insA | p.Tyr83Ter | stop_gained, frameshift_variant | 2/29 | 1 | NM_004646.4 | P2 | |
NPHS1 | ENST00000353632.6 | c.248_249insA | p.Tyr83Ter | stop_gained, frameshift_variant | 2/28 | 5 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461302Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726956
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:2
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 01, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 15, 2022 | This sequence change creates a premature translational stop signal (p.Tyr83*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital nephrotic syndrome (PMID: 15906409, 27594755). This variant is also known as c.248insA. ClinVar contains an entry for this variant (Variation ID: 56475). 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