19-35852304-GTCTCTCTCTCTC-GTCTCTCTCTCTCTC

Variant names:

• chr19-35852304-G-GTC
• rs139954720
• NM_004646.4:c.-469_-468dupGA

Variant summary

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

The NM_004646.4(NPHS1):​c.-469_-468dupGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000965 in 145,144 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00096 (0 hom., cov: 29)
• Consequence: NPHS1 NM_004646.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.-469_-468dupGA		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.-469_-468dupGA		5_prime_UTR_variant	Exon 1 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000591817.1	n.560-634_560-633dupGA		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.000979 AC: 142 AN: 145066 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000483

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0136

Gnomad SAS AF: 0.00131

Gnomad FIN AF: 0.000109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000504

Gnomad OTH AF: 0.00151

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

GnomAD4 genome AF: 0.000965 AC: 140 AN: 145144 Hom.: 0 Cov.: 29 AF XY: 0.00111 AC XY: 78 AN XY: 70562

African (AFR) AF: 0.000603 AC: 24 AN: 39830

American (AMR) AF: 0.000482 AC: 7 AN: 14518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3390

East Asian (EAS) AF: 0.0133 AC: 66 AN: 4974

South Asian (SAS) AF: 0.00131 AC: 6 AN: 4572

European-Finnish (FIN) AF: 0.000109 AC: 1 AN: 9158

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

European-Non Finnish (NFE) AF: 0.000504 AC: 33 AN: 65524

Other (OTH) AF: 0.00150 AC: 3 AN: 2000

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.0

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;