rs1555761935

Variant names:

• chr19-35841811-C-T
• rs1555761935
• NM_004646.4:c.2719G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004646.4(NPHS1):​c.2719G>A​(p.Ala907Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.10

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 3 ACMG points.

• PM1: In a disulfide_bond (size 57) in uniprot entity NPHN_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_004646.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26872104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.2719G>A	p.Ala907Thr	missense_variant	Exon 20 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.2719G>A	p.Ala907Thr	missense_variant	Exon 20 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.2719G>A	p.Ala907Thr	missense_variant	Exon 20 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727208

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 907 of the NPHS1 protein (p.Ala907Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with nephrotic syndrome (PMID: 12707396). ClinVar contains an entry for this variant (Variation ID: 556357). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPHS1 protein function with a positive predictive value of 80%. 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. -

Finnish congenital nephrotic syndrome Uncertain:1

Jan 26, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.27
Sift	Benign	0.52	T;T
Sift4G	Uncertain	0.026	D;D
Polyphen		0.48	P;.
Vest4		0.31
MutPred		0.52		Loss of stability (P = 0.128);Loss of stability (P = 0.128);
MVP		0.76
MPC		0.48
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.15
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555761935; hg19: chr19-36332713;