rs138173172
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2
The NM_004646.4(NPHS1):c.2746G>T(p.Ala916Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00285 in 1,614,122 control chromosomes in the GnomAD database, including 23 homozygotes. 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 0.0021 ( 2 hom., cov: 31)
Exomes 𝑓: 0.0029 ( 21 hom. )
Consequence
NPHS1
NM_004646.4 missense
NM_004646.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 3.75
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 Benign. Variant got -7 ACMG points.
PM1
In a disulfide_bond (size 57) in uniprot entity NPHN_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004646.4
BP4
Computational evidence support a benign effect (MetaRNN=0.023090273).
BP6
Variant 19-35841784-C-A is Benign according to our data. Variant chr19-35841784-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259491.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
BS2
High Homozygotes in GnomAd4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NPHS1 | NM_004646.4 | c.2746G>T | p.Ala916Ser | missense_variant | 20/29 | ENST00000378910.10 | NP_004637.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NPHS1 | ENST00000378910.10 | c.2746G>T | p.Ala916Ser | missense_variant | 20/29 | 1 | NM_004646.4 | ENSP00000368190.4 | ||
NPHS1 | ENST00000353632.6 | c.2746G>T | p.Ala916Ser | missense_variant | 20/28 | 5 | ENSP00000343634.5 |
Frequencies
GnomAD3 genomes AF: 0.00215 AC: 327AN: 152128Hom.: 2 Cov.: 31
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GnomAD3 exomes AF: 0.00191 AC: 480AN: 251432Hom.: 0 AF XY: 0.00199 AC XY: 270AN XY: 135884
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GnomAD4 exome AF: 0.00292 AC: 4269AN: 1461876Hom.: 21 Cov.: 32 AF XY: 0.00286 AC XY: 2080AN XY: 727240
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GnomAD4 genome AF: 0.00215 AC: 327AN: 152246Hom.: 2 Cov.: 31 AF XY: 0.00176 AC XY: 131AN XY: 74418
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Finnish congenital nephrotic syndrome Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 17, 2017 | - - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2023 | NPHS1: BS2 - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 24, 2022 | Variant summary: NPHS1 c.2746G>T (p.Ala916Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251432 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0019 vs 0.0034), allowing no conclusion about variant significance. c.2746G>T has been reported in the literature in settings of multigene panel testing of individuals with a variety of renal manifestations such as FSGS, minimal change nephrotic syndrome (example, Busher_2016, Gast_2016, Lehadenkari_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. At-least one co-occurrence with another pathogenic variant(s) as an alternative molecular basis of disease has been reported (Gilbert_2017, mitochondrial DNA, m.3243A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Kidney disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 01, 2019 | - - |
Congenital nephrotic syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
NPHS1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 21, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
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