rs1223946044
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_004646.4(NPHS1):c.2815+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00000124 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 splice_donor_region, intron
NM_004646.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9982
2
Clinical Significance
Conservation
PhyloP100: 4.10
Genes affected
NPHS1 (HGNC:7908): (NPHS1 adhesion molecule, nephrin) This gene encodes a member of the immunoglobulin family of cell adhesion molecules that functions in the glomerular filtration barrier in the kidney. The gene is primarily expressed in renal tissues, and the protein is a type-1 transmembrane protein found at the slit diaphragm of glomerular podocytes. The slit diaphragm is thought to function as an ultrafilter to exclude albumin and other plasma macromolecules in the formation of urine. Mutations in this gene result in Finnish-type congenital nephrosis 1, characterized by severe proteinuria and loss of the slit diaphragm and foot processes.[provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19-35841712-T-C is Pathogenic according to our data. Variant chr19-35841712-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554409.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.2815+3A>G | splice_donor_region_variant, intron_variant | ENST00000378910.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.2815+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_004646.4 | P2 | |||
NPHS1 | ENST00000353632.6 | c.2815+3A>G | splice_donor_region_variant, intron_variant | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152120Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461866Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727232
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 17, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 05, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at