NM_004646.4:c.1707C>A

Variant names:

• chr19-35845719-G-T
• rs386833888
• NM_004646.4:c.1707C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Moderate

The NM_004646.4(NPHS1):​c.1707C>A​(p.Ser569Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0300
• 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_004646.4 (NPHS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_004646.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-35845719-G-T is Pathogenic according to our data. Variant chr19-35845719-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 3254584.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.1707C>A	p.Ser569Arg	missense	Exon 13 of 29	NP_004637.1	O60500-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.1707C>A	p.Ser569Arg	missense	Exon 13 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.1647C>A	p.Ser549Arg	missense	Exon 13 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.1707C>A	p.Ser569Arg	missense	Exon 13 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Finnish congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.044
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.030
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.95		Gain of methylation at S569 (P = 0.0404)
MVP		0.89
MPC		2.1
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.97
gMVP		0.94
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs386833888; hg19: chr19-36336621;