chr19-35845719-G-T

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: 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 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 CliVar as Pathogenic. Clinvar id is 3254584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35845719-G-T is described in CliVar as Pathogenic. Clinvar id is 3254584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35845719-G-T is described in CliVar as Pathogenic. Clinvar id is 3254584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35845719-G-T is described in CliVar as Pathogenic. Clinvar id is 3254584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35845719-G-T is described in CliVar as Pathogenic. Clinvar id is 3254584.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.1707C>A	p.Ser569Arg	missense_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.1707C>A	p.Ser569Arg	missense_variant	Exon 13 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.1707C>A	p.Ser569Arg	missense_variant	Exon 13 of 28	5		ENSP00000343634.5
NPHS1	ENST00000585400.1	n.-209C>A		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: criteria provided, single submitter

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with nephrotic syndrome type 1 (MIM#256300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated CD80-like C2-set immunoglobulin domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in one homozygous individual with congenital nephrotic syndrome (PMID: 24392227). An alternative nucleotide change resulting in the same amino acid substitution (c.1707C>G, p.Ser569Arg) has previously been reported in one homozygous individual and one compound heterozygous fetus with congenital nephrotic syndrome (PMID: 17413422, PMID: 18503012). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies of patient cells showed absence of nephrin expression (PMID: 24392227). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.6	M;M
PhyloP100		-0.030
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.78
MutPred		0.95		Gain of methylation at S569 (P = 0.0404);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;