chr19-35825976-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004646.4(NPHS1):​c.*538G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 152,568 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 530 hom., cov: 32)
Exomes 𝑓: 0.089 ( 6 hom. )

Consequence

NPHS1
NM_004646.4 3_prime_UTR

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.07
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
Variant 19-35825976-C-T is Benign according to our data. Variant chr19-35825976-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHS1NM_004646.4 linkuse as main transcriptc.*538G>A 3_prime_UTR_variant 29/29 ENST00000378910.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHS1ENST00000378910.10 linkuse as main transcriptc.*538G>A 3_prime_UTR_variant 29/291 NM_004646.4 P2O60500-1

Frequencies

GnomAD3 genomes
AF:
0.0733
AC:
11135
AN:
151936
Hom.:
530
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0205
Gnomad AMI
AF:
0.132
Gnomad AMR
AF:
0.0773
Gnomad ASJ
AF:
0.113
Gnomad EAS
AF:
0.000580
Gnomad SAS
AF:
0.103
Gnomad FIN
AF:
0.0758
Gnomad MID
AF:
0.155
Gnomad NFE
AF:
0.104
Gnomad OTH
AF:
0.0869
GnomAD4 exome
AF:
0.0895
AC:
46
AN:
514
Hom.:
6
Cov.:
0
AF XY:
0.0899
AC XY:
25
AN XY:
278
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0481
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.146
Gnomad4 NFE exome
AF:
0.0982
Gnomad4 OTH exome
AF:
0.111
GnomAD4 genome
AF:
0.0732
AC:
11136
AN:
152054
Hom.:
530
Cov.:
32
AF XY:
0.0730
AC XY:
5423
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0205
Gnomad4 AMR
AF:
0.0772
Gnomad4 ASJ
AF:
0.113
Gnomad4 EAS
AF:
0.000582
Gnomad4 SAS
AF:
0.104
Gnomad4 FIN
AF:
0.0758
Gnomad4 NFE
AF:
0.104
Gnomad4 OTH
AF:
0.0859
Alfa
AF:
0.0264
Hom.:
15
Bravo
AF:
0.0682
Asia WGS
AF:
0.0420
AC:
147
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Congenital nephrotic syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.94
CADD
Benign
0.53
DANN
Benign
0.87

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: rs71354105; hg19: chr19-36316878; API