19-35852304-GTCTCTCTCTCTC-GTCTCTCTCTC

Variant names:

• chr19-35852304-GTC-G
• rs139954720
• NM_004646.4:c.-469_-468delGA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004646.4(NPHS1):​c.-469_-468delGA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0869 in 144,406 control chromosomes in the GnomAD database, including 967 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.087 (967 hom., cov: 29)
• Consequence: NPHS1 NM_004646.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.11
• 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]

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: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-35852304-GTC-G is Benign according to our data. Variant chr19-35852304-GTC-G is described in ClinVar as Benign. ClinVar VariationId is 1260809.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.-469_-468delGA		5_prime_UTR_variant	Exon 1 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.-469_-468delGA		5_prime_UTR_variant	Exon 1 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000591817.1	n.560-634_560-633delGA		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 12486 AN: 144336 Hom.: 948 Cov.: 29

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.0379

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.00663

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0359

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0729

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

GnomAD4 genome AF: 0.0869 AC: 12542 AN: 144406 Hom.: 967 Cov.: 29 AF XY: 0.0857 AC XY: 6012 AN XY: 70180

African (AFR) AF: 0.215 AC: 8551 AN: 39740

American (AMR) AF: 0.0473 AC: 683 AN: 14444

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 177 AN: 3374

East Asian (EAS) AF: 0.00665 AC: 33 AN: 4964

South Asian (SAS) AF: 0.0392 AC: 179 AN: 4564

European-Finnish (FIN) AF: 0.0498 AC: 444 AN: 8916

Middle Eastern (MID) AF: 0.0321 AC: 9 AN: 280

European-Non Finnish (NFE) AF: 0.0351 AC: 2288 AN: 65240

Other (OTH) AF: 0.0724 AC: 144 AN: 1988

Alfa AF: 0.00477 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome Benign:1

Aug 30, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1

Splicing

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

Other links and lift over

dbSNP: rs139954720; hg19: chr19-36343206;