rs386833941

Variant names:

• chr19-35826504-GAGAGGGCTCTTACACC-G
• rs386833941
• NM_004646.4:c.3720_*9delGGTGTAAGAGCCCTCT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_004646.4(NPHS1):​c.3720_*9delGGTGTAAGAGCCCTCT​(p.Leu1240fs) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L1240L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 frameshift, stop_lost
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.88
• 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]

NPHS1 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PP5: Variant 19-35826504-GAGAGGGCTCTTACACC-G is Pathogenic according to our data. Variant chr19-35826504-GAGAGGGCTCTTACACC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 56503.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.3720_*9delGGTGTAAGAGCCCTCT	p.Leu1240fs	frameshift_variant, stop_lost	Exon 29 of 29	ENST00000378910.10	NP_004637.1
NPHS1	NM_004646.4	c.3720_*9delGGTGTAAGAGCCCTCT		3_prime_UTR_variant	Exon 29 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.3720_*9delGGTGTAAGAGCCCTCT	p.Leu1240fs	frameshift_variant, stop_lost	Exon 29 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000378910.10	c.3720_*9delGGTGTAAGAGCCCTCT		3_prime_UTR_variant	Exon 29 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.3600_*9delGGTGTAAGAGCCCTCT	p.Leu1200fs	frameshift_variant, stop_lost	Exon 28 of 28	5		ENSP00000343634.5
NPHS1	ENST00000353632.6	c.3600_*9delGGTGTAAGAGCCCTCT		3_prime_UTR_variant	Exon 28 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1

-

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		1.9
Mutation Taster		=9/191	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs386833941; hg19: chr19-36317406;