rs386833917
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The ENST00000378910.10(NPHS1):c.2500G>T(p.Val834Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,816 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 (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NPHS1
ENST00000378910.10 missense
ENST00000378910.10 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 2.85
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000378910.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
Variant 19-35842385-C-A is Pathogenic according to our data. Variant chr19-35842385-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56478.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-35842385-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.2500G>T | p.Val834Phe | missense_variant | 18/29 | ENST00000378910.10 | NP_004637.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.2500G>T | p.Val834Phe | missense_variant | 18/29 | 1 | NM_004646.4 | ENSP00000368190 | P2 | |
NPHS1 | ENST00000353632.6 | c.2500G>T | p.Val834Phe | missense_variant | 18/28 | 5 | ENSP00000343634 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251032Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135728
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461672Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727156
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74334
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0918);Loss of MoRF binding (P = 0.0918);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at