rs76131336

Positions:

• chr19-35845358-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004646.4(NPHS1):​c.1930+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,614,158 control chromosomes in the GnomAD database, including 192 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 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (176 hom.)
• Consequence: NPHS1 NM_004646.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.139

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-35845358-G-A is Benign according to our data. Variant chr19-35845358-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 259485.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}. Variant chr19-35845358-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00996 (1517/152378) while in subpopulation NFE AF= 0.0159 (1080/68038). AF 95% confidence interval is 0.0151. There are 16 homozygotes in gnomad4. There are 678 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1930+10C>T		intron_variant		ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1930+10C>T		intron_variant		1	NM_004646.4	ENSP00000368190	P2
NPHS1	ENST00000585400.1	n.112+41C>T		intron_variant, non_coding_transcript_variant		1
NPHS1	ENST00000353632.6	c.1930+10C>T		intron_variant		5		ENSP00000343634	A2

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1516 AN: 152260 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00943 AC: 2369 AN: 251138 Hom.: 23 AF XY: 0.00936 AC XY: 1271 AN XY: 135848

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00333

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0139 AC: 20326 AN: 1461780 Hom.: 176 Cov.: 34 AF XY: 0.0137 AC XY: 9928 AN XY: 727194

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00342

Gnomad4 FIN exome AF: 0.00296

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.00996 AC: 1517 AN: 152378 Hom.: 16 Cov.: 32 AF XY: 0.00910 AC XY: 678 AN XY: 74514

Gnomad4 AFR AF: 0.00308

Gnomad4 AMR AF: 0.00927

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0132 Hom.: 8

Bravo AF: 0.0102

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2018	Variant summary: NPHS1 c.1930+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0093 in 276940 control chromosomes in the gnomAD database, including 27 homozygotes. The observed variant frequency is approximately 2.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1930+10C>T in individuals affected with Nephrotic Syndrome, Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Atypical hemolytic-uremic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.89

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: rs76131336; hg19: chr19-36336260;