rs200905486

chr19-35848707-C-Achr19-35848707-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_004646.4(NPHS1):c.1100G>T(p.Arg367Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R367C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a disulfide_bond (size 56) in uniprot entity NPHN_HUMAN there are 22 pathogenic changes around while only 6 benign (79%) in NM_004646.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35848708-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHS1	NM_004646.4	c.1100G>T	p.Arg367Leu	missense_variant	9/29	ENST00000378910.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHS1	ENST00000378910.10	c.1100G>T	p.Arg367Leu	missense_variant	9/29	1	NM_004646.4	P2
NPHS1	ENST00000353632.6	c.1100G>T	p.Arg367Leu	missense_variant	9/28	5		A2
NPHS1	ENST00000592132.1	n.107G>T		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.55	N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.99	D;.
Vest4		0.65
MutPred		0.72		Loss of MoRF binding (P = 0.033);Loss of MoRF binding (P = 0.033);
MVP		0.89
MPC		0.71
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.40
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200905486; hg19: chr19-36339609; COSMIC: COSV100799833; COSMIC: COSV100799833;