NM_004646.4:c.534delG
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004646.4(NPHS1):c.534delG(p.Thr179GlnfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NPHS1
NM_004646.4 frameshift
NM_004646.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.27
Publications
0 publications found
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]
NPHS1 Gene-Disease associations (from GenCC):
- congenital nephrotic syndrome, Finnish typeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
- familial idiopathic steroid-resistant nephrotic syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-35850437-TC-T is Pathogenic according to our data. Variant chr19-35850437-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004646.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NPHS1 | TSL:1 MANE Select | c.534delG | p.Thr179GlnfsTer9 | frameshift | Exon 5 of 29 | ENSP00000368190.4 | O60500-1 | ||
| NPHS1 | c.534delG | p.Thr179GlnfsTer9 | frameshift | Exon 5 of 29 | ENSP00000539165.1 | ||||
| NPHS1 | TSL:5 | c.534delG | p.Thr179GlnfsTer9 | frameshift | Exon 5 of 28 | ENSP00000343634.5 | O60500-2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152134
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727214 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461806
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727214
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33476
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39698
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111938
Other (OTH)
AF:
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.675
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74330 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
152134
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74330
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41398
American (AMR)
AF:
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5200
South Asian (SAS)
AF:
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68026
Other (OTH)
AF:
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Finnish congenital nephrotic syndrome (3)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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