chr19-35825985-G-A

Position:

• chr19-35825985-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004646.4(NPHS1):​c.*529C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 152,194 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: NPHS1 NM_004646.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.56

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0231 (3508/151718) while in subpopulation NFE AF= 0.0373 (2535/67924). AF 95% confidence interval is 0.0361. There are 54 homozygotes in gnomad4. There are 1635 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.*529C>T		3_prime_UTR_variant	29/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.*529C>T		3_prime_UTR_variant	29/29	1	NM_004646.4	ENSP00000368190	P2

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3508 AN: 151600 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.0210 AC: 10 AN: 476 Hom.: 0 Cov.: 0 AF XY: 0.0221 AC XY: 6 AN XY: 272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0263

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0231 AC: 3508 AN: 151718 Hom.: 54 Cov.: 32 AF XY: 0.0221 AC XY: 1635 AN XY: 74144

Gnomad4 AFR AF: 0.00662

Gnomad4 AMR AF: 0.0153

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0373

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0106 Hom.: 1

Bravo AF: 0.0214

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital nephrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.69

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: rs148755697; hg19: chr19-36316887;