rs114896482

chr19-35842487-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_004646.4(NPHS1):c.2398C>T(p.Arg800Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,614,076 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R800H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (8 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:4
• Conservation: PhyloP100: 1.34

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 -6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.025007755).
• 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.2398C>T	p.Arg800Cys	missense_variant	18/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.2398C>T	p.Arg800Cys	missense_variant	18/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.2398C>T	p.Arg800Cys	missense_variant	18/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 232 AN: 152094 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00771

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00229 AC: 576 AN: 251448 Hom.: 4 AF XY: 0.00223 AC XY: 303 AN XY: 135902

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00794

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.000945 AC: 1381 AN: 1461864 Hom.: 8 Cov.: 33 AF XY: 0.000899 AC XY: 654 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00630

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0156

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152212 Hom.: 3 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74416

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00773

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000616

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2018	- -

Familial idiopathic steroid-resistant nephrotic syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 06, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	16
Dann	Benign	0.74
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.20
Sift	Benign	0.17	T;T
Sift4G	Uncertain	0.033	D;D
Polyphen		0.011	B;.
Vest4		0.19
MVP		0.53
MPC		0.15
ClinPred		0.92	D
GERP RS		-0.19
Varity_R		0.22
gMVP		0.70

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: rs114896482; hg19: chr19-36333389; COSMIC: COSV62289431; COSMIC: COSV62289431;