chr19-35849092-C-G

Position:

• chr19-35849092-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004646.4(NPHS1):​c.896G>C​(p.Arg299Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.896G>C	p.Arg299Pro	missense_variant	8/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.896G>C	p.Arg299Pro	missense_variant	8/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.896G>C	p.Arg299Pro	missense_variant	8/28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457270 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725168

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Finnish congenital nephrotic syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 10, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.044
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.56
Sift	Benign	0.055	T;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.64
MutPred		0.66		Loss of MoRF binding (P = 0.0279);Loss of MoRF binding (P = 0.0279);
MVP		0.85
MPC		0.81
ClinPred		0.90	D
GERP RS		3.2
Varity_R		0.94
gMVP		0.89

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: rs755582721; hg19: chr19-36339994;