19-35852007-A-G

Position:

• chr19-35852007-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.-170T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 149,956 control chromosomes in the GnomAD database, including 4,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.16 (4242 hom., cov: 31)
• Consequence: NPHS1 NM_004646.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.63

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]

NPHS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-35852007-A-G is Benign according to our data. Variant chr19-35852007-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 369263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.-170T>C		5_prime_UTR_variant	1/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.-170T>C		5_prime_UTR_variant	1/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000591817.1	n.560-335T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23632 AN: 149864 Hom.: 4213 Cov.: 31

Gnomad AFR AF: 0.444

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0785

Gnomad ASJ AF: 0.0655

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0647

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0714

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.124

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.158 AC: 23708 AN: 149956 Hom.: 4242 Cov.: 31 AF XY: 0.155 AC XY: 11351 AN XY: 73030

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.0784

Gnomad4 ASJ AF: 0.0655

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0643

Gnomad4 FIN AF: 0.0433

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.122

Alfa AF: 0.121 Hom.: 497

Bravo AF: 0.172

Asia WGS AF: 0.108 AC: 377 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Finnish congenital nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.52
DANN	Benign	0.55

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs401824; hg19: chr19-36342909;