rs763972372

Variant names:

• chr19-35849060-C-A
• rs763972372
• NM_004646.4:c.928G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-35849060-C-A
• chr19-35849060-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_004646.4(NPHS1):​c.928G>T​(p.Asp310Tyr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D310A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.11
• 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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35849060-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 556151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 19-35849060-C-A is Pathogenic according to our data. Variant chr19-35849060-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2032904.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.928G>T	p.Asp310Tyr	missense_variant	Exon 8 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.928G>T	p.Asp310Tyr	missense_variant	Exon 8 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.928G>T	p.Asp310Tyr	missense_variant	Exon 8 of 28	5		ENSP00000343634.5
NPHS1	ENST00000592132.1	n.-66G>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. ClinVar contains an entry for this variant (Variation ID: 2032904). This variant has not been reported in the literature in individuals affected with NPHS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 310 of the NPHS1 protein (p.Asp310Tyr). This variant disrupts the p.Asp310 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16316524, 25729976, 25903641, 28204945). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		2.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.70
MutPred		0.79		Loss of disorder (P = 0.0474);Loss of disorder (P = 0.0474);
MVP		0.91
MPC		0.74
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.81
gMVP		0.96
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs763972372; hg19: chr19-36339962;