19-35852304-GTCTCTCTCTCTC-GTCTC

Variant names:

• chr19-35852304-GTCTCTCTC-G
• rs139954720
• NM_004646.4:c.-475_-468delGAGAGAGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_004646.4(NPHS1):​c.-475_-468delGAGAGAGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 145,164 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0042 (1 hom., cov: 29)
• Consequence: NPHS1 NM_004646.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 0.118
• Publications: 0 publications found

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]

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 19-35852304-GTCTCTCTC-G is Pathogenic according to our data. Variant chr19-35852304-GTCTCTCTC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56416.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.-475_-468delGAGAGAGA		5_prime_UTR_variant	Exon 1 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.-475_-468delGAGAGAGA		5_prime_UTR_variant	Exon 1 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000591817.1	n.560-640_560-633delGAGAGAGA		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.00418 AC: 607 AN: 145086 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000965

Gnomad ASJ AF: 0.00177

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.000218

Gnomad FIN AF: 0.00131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00801

Gnomad OTH AF: 0.000504

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

GnomAD4 genome AF: 0.00418 AC: 607 AN: 145164 Hom.: 1 Cov.: 29 AF XY: 0.00377 AC XY: 266 AN XY: 70574

African (AFR) AF: 0.00118 AC: 47 AN: 39830

American (AMR) AF: 0.000964 AC: 14 AN: 14522

Ashkenazi Jewish (ASJ) AF: 0.00177 AC: 6 AN: 3390

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4974

South Asian (SAS) AF: 0.000219 AC: 1 AN: 4572

European-Finnish (FIN) AF: 0.00131 AC: 12 AN: 9164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00801 AC: 525 AN: 65534

Other (OTH) AF: 0.000500 AC: 1 AN: 2000

Alfa AF: 0.00229 Hom.: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1 Uncertain:1

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

LRG_693t1:c.-475_-468del has an allele frequency of 0.009 in European (non-Finnish) subpopulation in the gnomAD database. It has been detected in one individual with congenital nephrotic syndrome, known as 489(del(GA)4) (PMID: 9915943). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP4. -

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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

Splicing

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

Other links and lift over

dbSNP: rs139954720; hg19: chr19-36343206;