NM_004646.4:c.-475_-468delGAGAGAGA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000964

Gnomad4 ASJ AF: 0.00177

Gnomad4 EAS AF: 0.000201

Gnomad4 SAS AF: 0.000219

Gnomad4 FIN AF: 0.00131

Gnomad4 NFE AF: 0.00801

Gnomad4 OTH AF: 0.000500

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

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs139954720; hg19: chr19-36343206;