NM_004646.4:c.3250dupG

Variant names:

• chr19-35831678-A-AC
• rs386833935
• NM_004646.4:c.3250dupG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_004646.4(NPHS1):​c.3250dupG​(p.Val1084GlyfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,606,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NPHS1 NM_004646.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 0.0300
• Publications: 9 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-35831678-A-AC is Pathogenic according to our data. Variant chr19-35831678-A-AC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004646.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.3250dupG	p.Val1084GlyfsTer12	frameshift	Exon 24 of 29	NP_004637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.3250dupG	p.Val1084GlyfsTer12	frameshift	Exon 24 of 29	ENSP00000368190.4
	NPHS1	ENST00000869106.1		c.3190dupG	p.Val1064GlyfsTer12	frameshift	Exon 24 of 29	ENSP00000539165.1
	NPHS1	ENST00000869107.1		c.3055dupG	p.Val1019GlyfsTer12	frameshift	Exon 22 of 27	ENSP00000539166.1

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150662 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 18 AN: 236910 AF XY: 0.0000545

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.0000906

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000941

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 221 AN: 1456162 Hom.: 0 Cov.: 34 AF XY: 0.000170 AC XY: 123 AN XY: 724184

African (AFR) AF: 0.0000903 AC: 3 AN: 33230

American (AMR) AF: 0.000137 AC: 6 AN: 43878

Ashkenazi Jewish (ASJ) AF: 0.0000768 AC: 2 AN: 26026

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39410

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85576

European-Finnish (FIN) AF: 0.0000569 AC: 3 AN: 52720

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1109574

Other (OTH) AF: 0.0000665 AC: 4 AN: 60118

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150662 Hom.: 0 Cov.: 31 AF XY: 0.0000408 AC XY: 3 AN XY: 73494

African (AFR) AF: 0.0000735 AC: 3 AN: 40838

American (AMR) AF: 0.00 AC: 0 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67670

Other (OTH) AF: 0.00 AC: 0 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Finnish congenital nephrotic syndrome (13)
4	-	-	not provided (4)
2	-	-	Nephrotic syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.030
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs386833935; hg19: chr19-36322580; COSMIC: COSV62289910;