19-35851677-G-C

Variant names:

• chr19-35851677-G-C
• rs114595892
• NM_004646.4:c.59-5C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004646.4(NPHS1):​c.59-5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00325 in 1,610,916 control chromosomes in the GnomAD database, including 158 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.018 (93 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (65 hom.)
• Consequence: NPHS1 NM_004646.4 splice_region, intron
• Scores: Splicing: ADA: 0.07373
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.853
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-35851677-G-C is Benign according to our data. Variant chr19-35851677-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259504.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004646.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.59-5C>G		splice_region intron	N/A	NP_004637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.59-5C>G		splice_region intron	N/A	ENSP00000368190.4
	NPHS1	ENST00000353632.6	TSL:5	c.59-5C>G		splice_region intron	N/A	ENSP00000343634.5
	NPHS1	ENST00000591817.1	TSL:5	n.560-5C>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2733 AN: 152222 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.0626

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00456 AC: 1093 AN: 239616 AF XY: 0.00333

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.000711

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000844

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.00172 AC: 2503 AN: 1458576 Hom.: 65 Cov.: 35 AF XY: 0.00150 AC XY: 1087 AN XY: 725368

African (AFR) AF: 0.0611 AC: 2040 AN: 33394

American (AMR) AF: 0.00435 AC: 192 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.000846 AC: 22 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.0000700 AC: 6 AN: 85712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53232

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1110516

Other (OTH) AF: 0.00332 AC: 200 AN: 60240

GnomAD4 genome AF: 0.0179 AC: 2733 AN: 152340 Hom.: 93 Cov.: 32 AF XY: 0.0172 AC XY: 1284 AN XY: 74502

African (AFR) AF: 0.0625 AC: 2597 AN: 41576

American (AMR) AF: 0.00621 AC: 95 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68022

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00502 Hom.: 6

Bravo AF: 0.0204

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	1	Finnish congenital nephrotic syndrome (2)
-	-	2	not provided (2)
-	-	1	Congenital nephrotic syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.85
PromoterAI		0.15	Neutral
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.074
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.19		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: rs114595892; hg19: chr19-36342579;