19-35845551-G-C

Variant names:

• chr19-35845551-G-C
• rs145554982
• NM_004646.4:c.1758-11C>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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:1 B:3
• Conservation: PhyloP100: -0.0210

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]

ACMG classification

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, Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1758-11C>G		intron_variant	Intron 13 of 28	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1758-11C>G		intron_variant	Intron 13 of 28	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1758-11C>G		intron_variant	Intron 13 of 27	5		ENSP00000343634.5
NPHS1	ENST00000585400.1	n.-41C>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152194 Hom.: 11 Cov.: 32

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.: 13 AF XY: 0.00704 AC XY: 917 AN XY: 130314

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.: 98 Cov.: 35 AF XY: 0.00870 AC XY: 6312 AN XY: 725666

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.: 11 Cov.: 32 AF XY: 0.00894 AC XY: 666 AN XY: 74464

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.: 0

Bravo AF: 0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHS1: BS2 -

May 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital nephrotic syndrome Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs145554982; hg19: chr19-36336453;