19-35851339-G-A

Variant names:

• chr19-35851339-G-A
• rs386833934
• NM_004646.4:c.320C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM5 PP3_Strong

The NM_004646.4(NPHS1):​c.320C>T​(p.Ala107Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,458 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A107T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 3.78
• Publications: 6 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]

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004646.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-35851340-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 56494.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.320C>T	p.Ala107Val	missense_variant	Exon 3 of 29	ENST00000378910.10	NP_004637.1
KIRREL2	XM_011527362.2	c.-568G>A		upstream_gene_variant			XP_011525664.1
KIRREL2	XM_011527363.2	c.-559G>A		upstream_gene_variant			XP_011525665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.320C>T	p.Ala107Val	missense_variant	Exon 3 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.320C>T	p.Ala107Val	missense_variant	Exon 3 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249102 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461458 Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7 AN XY: 727012

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111832

Other (OTH) AF: 0.0000166 AC: 1 AN: 60364

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000914 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Pathogenic:1 Uncertain:3

Dec 03, 2018

Vasylyeva lab, Texas Tech University Health Sciences Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Ala107Val variant in NPHS1 was identified by our study in the compound heterozygous state, with a VUS, in one individual with nephrotic syndrome. This variant was seen in 0.006511% (2/30718) of South Asian chromosomes and 0.0009039% (1/110628) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386833934). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Ala107Val variant in NPHS1 has been reported in two unrelated individuals in the heterozygous state, one with a splice site variant in trans, with nephrotic syndrome (PMID: 20172850). The presence of this variant in combination with a splice site variant and in an individual with nephrotic syndrome increases the likelihood that the p.Ala107Val variant is pathogenic. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3_Supporting (Richards 2015). -

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Pathogenic	3.8	H;H
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.96		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.89
MPC		0.69
ClinPred		0.98	D
GERP RS		5.9
PromoterAI		0.078	Neutral
Varity_R		0.67
gMVP		0.82
Mutation Taster		=10/90	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: rs386833934; hg19: chr19-36342241;