rs145125791

chr19-35850409-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_004646.4(NPHS1):c.563A>T(p.Asn188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00799 in 1,614,106 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (66 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.514

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 -7 ACMG points.

• PM1: In a disulfide_bond (size 57) in uniprot entity NPHN_HUMAN there are 16 pathogenic changes around while only 6 benign (73%) in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.025585592).
• BP6: Variant 19-35850409-T-A is Benign according to our data. Variant chr19-35850409-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282372.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3, Likely_benign=7}. Variant chr19-35850409-T-A is described in Lovd as [Benign]. Variant chr19-35850409-T-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.563A>T	p.Asn188Ile	missense_variant	5/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.563A>T	p.Asn188Ile	missense_variant	5/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.563A>T	p.Asn188Ile	missense_variant	5/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 915 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00643

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00605 AC: 1521 AN: 251492 Hom.: 5 AF XY: 0.00636 AC XY: 864 AN XY: 135918

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00428

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00591

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00927

Gnomad OTH exome AF: 0.00700

GnomAD4 exome AF: 0.00820 AC: 11985 AN: 1461836 Hom.: 66 Cov.: 31 AF XY: 0.00806 AC XY: 5865 AN XY: 727226

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00539

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.00945

Gnomad4 OTH exome AF: 0.00782

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74448

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00726

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00956

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00837 Hom.: 1

Bravo AF: 0.00631

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00977 AC: 84

ExAC AF: 0.00619 AC: 751

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Finnish congenital nephrotic syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 22, 2017	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2021	Variant summary: NPHS1 c.563A>T (p.Asn188Ile) results in a non-conservative amino acid change located in the CD80-like, immunoglobulin C2-set domain (IPR013162) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.006 in 251492 control chromosomes, predominantly at a frequency of 0.0093 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.563A>T has been reported in the literature in individuals affected with a variety of renal phenotypes such as congenital FSGS (example Koziell_2002), Alport syndrome (example, Gibson_2013, Chatterjee_2013) and in settings of multigene panel testing for pediatric Nephrotic syndrome (example Abid_2018). In families with this variant, a clear lack of segregation of this variant with the underlying clinical phenotype of Alport syndrome attributed to a causative variant in the COL4A5 gene was noted (example, Gibson_2013, Chatterjee_2013). Multiple reports of co-occurrences with other pathogenic variant(s) have been reported (homozygous NPHS2 (436)delA, in two siblings with FSGS, Koziell_2002; COL4A5 c.973G>A, p.Gly325Arg, Gibson_2013; COL4A5 c.3482G>A, p.Gly1161Glu, Chatterjee_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 citing a predominant classification of likely benign (n=4)/benign (n=2), VUS (n=1). Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	NPHS1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Congenital nephrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 17, 2022

- -

NPHS1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	13
Dann	Benign	0.96
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.25
Sift	Benign	0.56	T;T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.57	P;.
Vest4		0.79
MVP		0.83
MPC		0.44
ClinPred		0.0048	T
GERP RS		2.2
Varity_R		0.22
gMVP		0.53

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: rs145125791; hg19: chr19-36341311; COSMIC: COSV105273982; COSMIC: COSV105273982;