Variant 19-35844144-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_004646.4(NPHS1):c.2171C>G(p.Ser724Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,428 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 (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NPHS1
NM_004646.4 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.80

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]

NPHS1 links:

NPHS1 (HGNC:):

NPHS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

PP5

Variant 19-35844144-G-C is Pathogenic according to our data. Variant chr19-35844144-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56465.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-35844144-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.2171C>G	p.Ser724Cys	missense_variant	16/29	ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.2171C>G	p.Ser724Cys	missense_variant	16/29	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000585400.1 linkuse as main transcript	n.353C>G		non_coding_transcript_exon_variant	3/3	1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.2171C>G	p.Ser724Cys	missense_variant	16/28	5		ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000405

AC:

AN:

247166

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457428

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725246

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Finnish congenital nephrotic syndrome

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.96

D;.

Vest4

0.77

MutPred

0.70

Loss of disorder (P = 0.0077);Loss of disorder (P = 0.0077);

MVP

0.88

MPC

1.4

ClinPred

0.94

GERP RS

4.8

Varity_R

0.32

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over