rs138173172

chr19-35841784-C-Achr19-35841784-C-T

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.2746G>T(p.Ala916Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00285 in 1,614,122 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A916T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (21 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 3.75

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 domain Ig-like C2-type 8 (size 101) in uniprot entity NPHN_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.023090273).
• BP6: Variant 19-35841784-C-A is Benign according to our data. Variant chr19-35841784-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259491.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.2746G>T	p.Ala916Ser	missense_variant	20/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.2746G>T	p.Ala916Ser	missense_variant	20/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.2746G>T	p.Ala916Ser	missense_variant	20/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152128 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251432 Hom.: 0 AF XY: 0.00199 AC XY: 270 AN XY: 135884

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00292 AC: 4269 AN: 1461876 Hom.: 21 Cov.: 32 AF XY: 0.00286 AC XY: 2080 AN XY: 727240

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152246 Hom.: 2 Cov.: 31 AF XY: 0.00176 AC XY: 131 AN XY: 74418

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00290 Hom.: 1

Bravo AF: 0.00190

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00197 AC: 239

EpiCase AF: 0.00360

EpiControl AF: 0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 17, 2017	- -

not provided Benign:2

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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 24, 2022

Variant summary: NPHS1 c.2746G>T (p.Ala916Ser) results in a conservative amino acid change located in the Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251432 control chromosomes, predominantly at a frequency of 0.0034 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 (0.0019 vs 0.0034), allowing no conclusion about variant significance. c.2746G>T has been reported in the literature in settings of multigene panel testing of individuals with a variety of renal manifestations such as FSGS, minimal change nephrotic syndrome (example, Busher_2016, Gast_2016, Lehadenkari_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Nephrotic Syndrome, Type 1. At-least one co-occurrence with another pathogenic variant(s) as an alternative molecular basis of disease has been reported (Gilbert_2017, mitochondrial DNA, m.3243A>G), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Kidney disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2019

- -

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

NPHS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2021

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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.93	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.032	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.66
MVP		0.88
MPC		0.50
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.74

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: rs138173172; hg19: chr19-36332686;