rs386833939

chr19-35830956-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_004646.4(NPHS1):c.3482G>T(p.Gly1161Val) 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. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1161S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 missense, splice_region
• Scores: Splicing: ADA: 0.9363
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.680

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35830956-C-A is Pathogenic according to our data. Variant chr19-35830956-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56501.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-35830956-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.3482G>T	p.Gly1161Val	missense_variant, splice_region_variant	28/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.3482G>T	p.Gly1161Val	missense_variant, splice_region_variant	28/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.3362G>T	p.Gly1121Val	missense_variant, splice_region_variant	27/28	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.0013	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.59	P;.
Vest4		0.60
MutPred		0.32		Loss of disorder (P = 0.0926);.;
MVP		0.79
MPC		0.15
ClinPred		0.80	D
GERP RS		0.19
Varity_R		0.12
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -9

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833939; hg19: chr19-36321858;