19-35831116-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM5 BP4_Strong BP6_Very_Strong BS2

The NM_004646.4(NPHS1):c.3418C>A(p.Arg1140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,613,946 control chromosomes in the GnomAD database, including 10 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1140H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.89

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 -14 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35831116-G-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.009340763).
• BP6: Variant 19-35831116-G-T is Benign according to our data. Variant chr19-35831116-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 259498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831116-G-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3418C>A	p.Arg1140Ser	missense_variant	27/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3418C>A	p.Arg1140Ser	missense_variant	27/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3298C>A	p.Arg1100Ser	missense_variant	26/28	5		A2

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152094 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.000983 AC: 247 AN: 251274 Hom.: 1 AF XY: 0.000736 AC XY: 100 AN XY: 135842

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461734 Hom.: 4 Cov.: 34 AF XY: 0.000355 AC XY: 258 AN XY: 727182

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152212 Hom.: 6 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74428

Gnomad4 AFR AF: 0.0129

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000424 Hom.: 0

Bravo AF: 0.00416

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	This variant is associated with the following publications: (PMID: 26990548) -

Finnish congenital nephrotic syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 03, 2020	- -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.62	N;N
REVEL	Benign	0.084
Sift	Benign	0.079	T;T
Sift4G	Uncertain	0.044	D;D
Polyphen		0.010	B;.
Vest4		0.35
MVP		0.72
MPC		0.12
ClinPred		0.018	T
GERP RS		1.6
Varity_R		0.072
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs143092783; hg19: chr19-36322018; COSMIC: COSV62286682;