rs730880174

Variant names:

• chr19-35845670-T-C
• rs730880174
• NM_004646.4:c.1756A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004646.4(NPHS1):​c.1756A>G​(p.Arg586Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 missense, splice_region
• Scores: Splicing: ADA: 0.9983
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.54
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-35845670-T-C is Pathogenic according to our data. Variant chr19-35845670-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 180463.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.1756A>G	p.Arg586Gly	missense_variant, splice_region_variant	Exon 13 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.1756A>G	p.Arg586Gly	missense_variant, splice_region_variant	Exon 13 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1756A>G	p.Arg586Gly	missense_variant, splice_region_variant	Exon 13 of 28	5		ENSP00000343634.5
NPHS1	ENST00000585400.1	n.-160A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1

May 16, 2014

Blueprint Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Benign	0.87
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.41
Sift	Benign	0.46	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.0020	B;.
Vest4		0.23
MutPred		0.82		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.84
MPC		1.1
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.80
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.78		Position offset: -1

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

Other links and lift over

dbSNP: rs730880174; hg19: chr19-36336572;