19-35831368-C-T

Variant names:

• chr19-35831368-C-T
• rs2071327
• NM_004646.4:c.3315G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.3315G>A​(p.Ser1105Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,270 control chromosomes in the GnomAD database, including 122,372 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9723 hom., cov: 30)
  • Exomes 𝑓: 0.39 (112649 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.20

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.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-35831368-C-T is Benign according to our data. Variant chr19-35831368-C-T is described in ClinVar as [Benign]. Clinvar id is 259497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35831368-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.3315G>A	p.Ser1105Ser	synonymous_variant	Exon 26 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.3315G>A	p.Ser1105Ser	synonymous_variant	Exon 26 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.3195G>A	p.Ser1065Ser	synonymous_variant	Exon 25 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49111 AN: 151728 Hom.: 9718 Cov.: 30

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.351

GnomAD3 exomes AF: 0.400 AC: 100518 AN: 251432 Hom.: 21847 AF XY: 0.402 AC XY: 54616 AN XY: 135894

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.409

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.385 AC: 563048 AN: 1461424 Hom.: 112649 Cov.: 43 AF XY: 0.387 AC XY: 281213 AN XY: 727048

Gnomad4 AFR exome AF: 0.0880

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.349

Gnomad4 EAS exome AF: 0.655

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.378

GnomAD4 genome AF: 0.323 AC: 49121 AN: 151846 Hom.: 9723 Cov.: 30 AF XY: 0.332 AC XY: 24645 AN XY: 74164

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.345

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.357

Alfa AF: 0.356 Hom.: 12905

Bravo AF: 0.308

Asia WGS AF: 0.546 AC: 1896 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.366

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Jan 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 65% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 60. Only high quality variants are reported. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome Benign:3

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital nephrotic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2071327; hg19: chr19-36322270;