rs77309273

Positions:

• chr19-35826654-C-A
• chr19-35826654-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.3595-9G>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,613,580 control chromosomes in the GnomAD database, including 2,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1894 hom.)
• Consequence: NPHS1 NM_004646.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003676
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.301

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35826654-C-A is Benign according to our data. Variant chr19-35826654-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 259501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35826654-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3595-9G>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3595-9G>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3475-9G>T		splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6040 AN: 152034 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.00771

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0417 AC: 10382 AN: 249222 Hom.: 335 AF XY: 0.0420 AC XY: 5660 AN XY: 134896

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0418

GnomAD4 exome AF: 0.0459 AC: 67018 AN: 1461428 Hom.: 1894 Cov.: 31 AF XY: 0.0458 AC XY: 33273 AN XY: 727008

Gnomad4 AFR exome AF: 0.00682

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0488

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0497

Gnomad4 OTH exome AF: 0.0392

GnomAD4 genome AF: 0.0397 AC: 6038 AN: 152152 Hom.: 180 Cov.: 32 AF XY: 0.0417 AC XY: 3099 AN XY: 74388

Gnomad4 AFR AF: 0.00768

Gnomad4 AMR AF: 0.0277

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.113

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0340

Alfa AF: 0.0402 Hom.: 95

Bravo AF: 0.0315

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 26, 2018	- -

Finnish congenital nephrotic syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2017

- -

Congenital nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.0
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs77309273; hg19: chr19-36317556;