rs115444936

Positions:

• chr19-35845788-A-C
• chr19-35845788-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_004646.4(NPHS1):​c.1638T>G​(p.Thr546Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,612,662 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.88

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35845788-A-C is Benign according to our data. Variant chr19-35845788-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 328869.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1638T>G	p.Thr546Thr	synonymous_variant	13/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1638T>G	p.Thr546Thr	synonymous_variant	13/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1638T>G	p.Thr546Thr	synonymous_variant	13/28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00167 AC: 418 AN: 250686 Hom.: 3 AF XY: 0.00184 AC XY: 249 AN XY: 135612

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00260 AC: 3796 AN: 1460418 Hom.: 9 Cov.: 34 AF XY: 0.00252 AC XY: 1833 AN XY: 726226

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74450

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00167

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NPHS1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 17, 2016	Variant summary: The NPHS1 c.1638T>G (p.Thr546Thr) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC with an allele frequency of 195/119054 (1/610 including 2 homozygotes), predominantly observed in the European (Non-Finnish) cohort, 166/65658 (1/395, 1 homozygote), which does not exceed the estimated maximal expected allele frequency for a pathogenic NPHS1 variant of 1/298. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as "Likely Benign." -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 15, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	- -

Congenital nephrotic syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Finnish congenital nephrotic syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.66

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: rs115444936; hg19: chr19-36336690;