19-35845551-G-C

Position:

chr19-35845551-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004646.4(NPHS1):c.1758-11C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00883 in 1,611,298 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0077 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 98 hom. )

Consequence

NPHS1
NM_004646.4 intron

Scores

Splicing: ADA: 0.0007102

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.0210

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:

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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=-0.8).

BP6

Variant 19-35845551-G-C is Benign according to our data. Variant chr19-35845551-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328868.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4 linkuse as main transcript	c.1758-11C>G		intron_variant		ENST00000378910.10	NP_004637.1	O60500-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
NPHS1	ENST00000378910.10 linkuse as main transcript	c.1758-11C>G	intron_variant	1	NM_004646.4	ENSP00000368190.4	O60500-1
NPHS1	ENST00000353632.6 linkuse as main transcript	c.1758-11C>G	intron_variant	5		ENSP00000343634.5	O60500-2
NPHS1	ENST00000585400.1 linkuse as main transcript	n.-41C>G	upstream_gene_variant	1

Frequencies

GnomAD3 genomes

AF:

0.00769

AC:

1170

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0399

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00867

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00730

AC:

1740

AN:

238332

Hom.:

AF XY:

0.00704

AC XY:

917

AN XY:

130314

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00205

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.000397

Gnomad FIN exome

AF:

0.0363

Gnomad NFE exome

AF:

0.00833

Gnomad OTH exome

AF:

0.00395

GnomAD4 exome

AF:

0.00895

AC:

13062

AN:

1458986

Hom.:

Cov.:

AF XY:

0.00870

AC XY:

6312

AN XY:

725666

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00135

Gnomad4 ASJ exome

AF:

0.00200

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.000407

Gnomad4 FIN exome

AF:

0.0356

Gnomad4 NFE exome

AF:

0.00952

Gnomad4 OTH exome

AF:

0.00693

GnomAD4 genome

AF:

0.00769

AC:

1171

AN:

152312

Hom.:

Cov.:

AF XY:

0.00894

AC XY:

666

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.0399

Gnomad4 NFE

AF:

0.00867

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00682

Hom.:

Bravo

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	NPHS1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The NPHS1 c.1758-11C>G variant involves the alteration of a non-conserved nucleotide in the intronic region . One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 649/102412 control chromosomes (1 homozygote), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.035667 (160/4486). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic NPHS1 variant in Finnish population (0.0039, see calculation in additional comments), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in a patient with end stage renal disease who also carries a pathogenic WT1 variant (c.1385G>A/p.Arg462Gln). Although one other clinical diagnostic laboratory classified this variant as uncertain significance, multiple lines of evidence support neutrality of this variant. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Congenital nephrotic syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This 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

-0.80

CADD

Benign

1.4

DANN

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.17

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