rs143092783

chr19-35831116-G-Achr19-35831116-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004646.4(NPHS1):c.3418C>T(p.Arg1140Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1140H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 1.89

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2733047).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3418C>T	p.Arg1140Cys	missense_variant	27/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3418C>T	p.Arg1140Cys	missense_variant	27/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3298C>T	p.Arg1100Cys	missense_variant	26/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251274 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135842

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461734 Hom.: 0 Cov.: 34 AF XY: 0.0000853 AC XY: 62 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74300

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000113

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_004646.3(NPHS1):c.3418C>T(R1140C) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. R1140C has been observed in cases with relevant disease (PMID: 26346198, 20172850, 9915943). Functional assessments of this variant are available in the literature (PMID: 24142548, 15496146, 11726550). R1140C has been observed in population frequency databases (gnomAD NFE 0.02%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.3418C>T(R1140C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 10, 2022	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1140 of the NPHS1 protein (p.Arg1140Cys). This variant is present in population databases (rs143092783, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of NPHS1-related conditions (PMID: 9915943, 26346198). ClinVar contains an entry for this variant (Variation ID: 56500). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect NPHS1 function (PMID: 11726550, 24142548). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.73	P;.
Vest4		0.34
MVP		0.76
MPC		0.24
ClinPred		0.048	T
GERP RS		1.6
Varity_R		0.093
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs143092783; hg19: chr19-36322018;