rs537783084

Positions:

• chr19-35830894-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004646.4(NPHS1):​c.3544A>G​(p.Thr1182Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. T1182M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.109

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028898656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3544A>G	p.Thr1182Ala	missense_variant	28/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3544A>G	p.Thr1182Ala	missense_variant	28/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3424A>G	p.Thr1142Ala	missense_variant	27/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251486 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000725 AC: 106 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 81 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74454

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_004646.3(NPHS1):c.3544A>G(T1182A) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. T1182A has been observed in cases with relevant disease (PMID: 22565185, 26248470). Functional assessments of this variant are not available in the literature. T1182A has been observed in population frequency databases (gnomAD: SAS 0.1%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.3544A>G(T1182A) 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	Baylor Genetics	Jul 15, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	Reported with a second variant (phase unknown) in a patient with congential nephrotic syndrome in published literature (Weber et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22565185, 26248470) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces threonine with alanine at codon 1182 of the NPHS1 protein (p.Thr1182Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs537783084, ExAC 0.1%). This missense change has been observed in individuals with steroid resistant nephrotic syndrome (PMID: 22565185, 26248470). ClinVar contains an entry for this variant (Variation ID: 496272). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The NPHS1 c.3544A>G (p.Thr1182Ala) variant involves the alteration of a non-conserved nucleotide and 4/5 in silico tools predict a benign outcome for this variant. However, there are no functional studies to confirm these prediction results. This variant is located in a region that binds with NPHS2 protein (UniProt). This variant was found in 25/121708 control chromosomes at a frequency of 0.0002054, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541). This variant has been reported in two patients with nephrotic syndrome, one in homozygous state and other in compound heterozygousity with a novel variant p.Ser572Gly (Abid_2012, Weber_2016). An internal sample carrying this variant homozygously in cis with a known pathgenic variant, p.R1109*. Without additional segregational and functional studies the currently available genotype-phenotype and population data are not conclusive enough to establish the pathogenicity. Therefore, this variant has currently been classified as Variant of Uncertain Signficance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.35
DANN	Benign	0.23
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.042
Sift	Benign	0.92	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.22		Loss of glycosylation at T1182 (P = 0.0228);.;
MVP		0.47
MPC		0.10
ClinPred		0.0075	T
GERP RS		-3.4
Varity_R		0.021
gMVP		0.096

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs537783084; hg19: chr19-36321796;