chr19-35845538-A-C

Position:

• chr19-35845538-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004646.4(NPHS1):​c.1760T>G​(p.Leu587Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NPHS1 NM_004646.4 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.31

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Ig-like C2-type 6 (size 91) in uniprot entity NPHN_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_004646.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-35845538-A-C is Pathogenic according to our data. Variant chr19-35845538-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 56450.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35845538-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1760T>G	p.Leu587Arg	missense_variant, splice_region_variant	14/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1760T>G	p.Leu587Arg	missense_variant, splice_region_variant	14/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1760T>G	p.Leu587Arg	missense_variant, splice_region_variant	14/28	5		ENSP00000343634.5
NPHS1	ENST00000585400.1	n.-28T>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459282 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725868

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2023	Variant summary: NPHS1 c.1760T>G (p.Leu587Arg) results in a non-conservative amino acid change located in the CD80-like, immunoglobulin C2-set domain (IPR013162) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 238368 control chromosomes (gnomAD). c.1760T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with Nephrotic Syndrome (e.g. Schoeb_2010, Warejko_2018, Chen_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31456999, 20172850, 29127259). One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nephrotic syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Nov 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.95		Gain of methylation at K582 (P = 0.0283);Gain of methylation at K582 (P = 0.0283);
MVP		0.97
MPC		2.3
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.95
gMVP		0.91

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

Other links and lift over

dbSNP: rs386833892; hg19: chr19-36336440;