chr19-35825808-T-C

Position:

• chr19-35825808-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004646.4(NPHS1):​c.*706A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 152,270 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.030 (90 hom., cov: 32)
• Consequence: NPHS1 NM_004646.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.535

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-35825808-T-C is Benign according to our data. Variant chr19-35825808-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 328846.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0304 (4636/152270) while in subpopulation NFE AF= 0.043 (2926/68020). AF 95% confidence interval is 0.0417. There are 90 homozygotes in gnomad4. There are 2345 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 90 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.*706A>G		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.*706A>G		3_prime_UTR_variant	29/29	1	NM_004646.4	ENSP00000368190	P2

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4638 AN: 152152 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.00652

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.0257

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.0673

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0430

Gnomad OTH AF: 0.0301

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0304 AC: 4636 AN: 152270 Hom.: 90 Cov.: 32 AF XY: 0.0315 AC XY: 2345 AN XY: 74454

Gnomad4 AFR AF: 0.00650

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0467

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.0673

Gnomad4 NFE AF: 0.0430

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0437 Hom.: 24

Bravo AF: 0.0258

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital nephrotic syndrome Benign:1

Likely benign, 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 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	-0.78
CADD	Benign	5.9
DANN	Benign	0.75

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs80296922; hg19: chr19-36316710;