19-35825985-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_004646.4(NPHS1):​c.*529C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 152,194 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.023 ( 54 hom., cov: 32)
Exomes 𝑓: 0.021 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 3_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.56
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 Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-1.02).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3508/151718) while in subpopulation NFE AF= 0.0373 (2535/67924). AF 95% confidence interval is 0.0361. There are 54 homozygotes in gnomad4. There are 1635 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPHS1NM_004646.4 linkuse as main transcriptc.*529C>T 3_prime_UTR_variant 29/29 ENST00000378910.10 NP_004637.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPHS1ENST00000378910.10 linkuse as main transcriptc.*529C>T 3_prime_UTR_variant 29/291 NM_004646.4 ENSP00000368190 P2O60500-1

Frequencies

GnomAD3 genomes
AF:
0.0231
AC:
3508
AN:
151600
Hom.:
54
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00664
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0154
Gnomad ASJ
AF:
0.0265
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00499
Gnomad FIN
AF:
0.0308
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0373
Gnomad OTH
AF:
0.0125
GnomAD4 exome
AF:
0.0210
AC:
10
AN:
476
Hom.:
0
Cov.:
0
AF XY:
0.0221
AC XY:
6
AN XY:
272
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0288
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0263
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0205
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0231
AC:
3508
AN:
151718
Hom.:
54
Cov.:
32
AF XY:
0.0221
AC XY:
1635
AN XY:
74144
show subpopulations
Gnomad4 AFR
AF:
0.00662
Gnomad4 AMR
AF:
0.0153
Gnomad4 ASJ
AF:
0.0265
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00499
Gnomad4 FIN
AF:
0.0308
Gnomad4 NFE
AF:
0.0373
Gnomad4 OTH
AF:
0.0123
Alfa
AF:
0.0106
Hom.:
1
Bravo
AF:
0.0214
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital nephrotic syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-1.0
CADD
Benign
1.1
DANN
Benign
0.69

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: rs148755697; hg19: chr19-36316887; API