rs386833902

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_004646.4(NPHS1):​c.2126T>G​(p.Val709Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,459,798 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 (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

10
7
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.44
Variant links:
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 Pathogenic. Variant got 12 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936
PP5
Variant 19-35844189-A-C is Pathogenic according to our data. Variant chr19-35844189-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35844189-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHS1NM_004646.4 linkc.2126T>G p.Val709Gly missense_variant Exon 16 of 29 ENST00000378910.10 NP_004637.1 O60500-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHS1ENST00000378910.10 linkc.2126T>G p.Val709Gly missense_variant Exon 16 of 29 1 NM_004646.4 ENSP00000368190.4 O60500-1
NPHS1ENST00000585400.1 linkn.308T>G non_coding_transcript_exon_variant Exon 3 of 3 1
NPHS1ENST00000353632.6 linkc.2126T>G p.Val709Gly missense_variant Exon 16 of 28 5 ENSP00000343634.5 O60500-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1459798
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
726388
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000126
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:3
-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.
Eigen
Pathogenic
0.72
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.60
T;T
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Uncertain
0.28
D
MutationAssessor
Pathogenic
3.5
H;H
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-5.9
D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.77
MutPred
0.72
Loss of stability (P = 0.0042);Loss of stability (P = 0.0042);
MVP
0.93
MPC
2.1
ClinPred
0.99
D
GERP RS
4.7
Varity_R
0.73
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833902; hg19: chr19-36335091; API