chr19-35839554-C-G

Position:

• chr19-35839554-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BS1 BS2

The NM_004646.4(NPHS1):​c.2869G>C​(p.Val957Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,614,168 control chromosomes in the GnomAD database, including 13 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V957M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00072 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (9 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 3.23

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 -9 ACMG points.

• PM1: In a domain Fibronectin type-III (size 95) in uniprot entity NPHN_HUMAN there are 13 pathogenic changes around while only 5 benign (72%) in NM_004646.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35839553-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 931014.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.018834054).
• BP6: Variant 19-35839554-C-G is Benign according to our data. Variant chr19-35839554-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225423.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=3}. Variant chr19-35839554-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000641 (937/1461886) while in subpopulation EAS AF= 0.0184 (729/39700). AF 95% confidence interval is 0.0173. There are 9 homozygotes in gnomad4_exome. There are 474 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.2869G>C	p.Val957Leu	missense_variant	21/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.2869G>C	p.Val957Leu	missense_variant	21/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.2869G>C	p.Val957Leu	missense_variant	21/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00106 AC: 267 AN: 251432 Hom.: 0 AF XY: 0.000949 AC XY: 129 AN XY: 135900

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0116

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000641 AC: 937 AN: 1461886 Hom.: 9 Cov.: 32 AF XY: 0.000652 AC XY: 474 AN XY: 727244

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0184

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74454

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0135

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000506 Hom.: 1

Bravo AF: 0.000627

ExAC AF: 0.00119 AC: 144

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2017	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 05, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NPHS1: PM5, BP4, BS1 -

Congenital nephrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.3	L;L
MutationTaster	Benign	0.90	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.029	D;T
Polyphen		1.0	D;.
Vest4		0.79
MutPred		0.86		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.80
MPC		0.33
ClinPred		0.043	T
GERP RS		4.3
Varity_R		0.30
gMVP		0.55

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: rs114849139; hg19: chr19-36330456;