chr19-35848629-C-T

Variant names:

• chr19-35848629-C-T
• rs140808195
• NM_004646.4:c.1170+8G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004646.4(NPHS1):​c.1170+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00643 in 1,613,042 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 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 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (42 hom.)
• Consequence: NPHS1 NM_004646.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006057
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.635
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-35848629-C-T is Benign according to our data. Variant chr19-35848629-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259480.
• BS2: High Homozygotes in GnomAdExome4 at 42 AR,AD gene

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.1170+8G>A		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.1170+8G>A		splice_region intron	N/A	ENSP00000368190.4
	NPHS1	ENST00000353632.6	TSL:5	c.1170+8G>A		splice_region intron	N/A	ENSP00000343634.5
	NPHS1	ENST00000592132.1	TSL:3	n.177+8G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00392 AC: 982 AN: 250218 AF XY: 0.00384

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.000955

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000979

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00670 AC: 9785 AN: 1460794 Hom.: 42 Cov.: 32 AF XY: 0.00642 AC XY: 4662 AN XY: 726706

African (AFR) AF: 0.00138 AC: 46 AN: 33448

American (AMR) AF: 0.000716 AC: 32 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 67 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000917 AC: 79 AN: 86190

European-Finnish (FIN) AF: 0.00126 AC: 67 AN: 53348

Middle Eastern (MID) AF: 0.000198 AC: 1 AN: 5058

European-Non Finnish (NFE) AF: 0.00834 AC: 9275 AN: 1111942

Other (OTH) AF: 0.00362 AC: 218 AN: 60288

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.00386 AC XY: 287 AN XY: 74434

African (AFR) AF: 0.00147 AC: 61 AN: 41544

American (AMR) AF: 0.00261 AC: 40 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00669 AC: 455 AN: 68008

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00576 Hom.: 3

Bravo AF: 0.00386

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 3

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

Other links and lift over

dbSNP: rs140808195; hg19: chr19-36339531;