chr19-35826654-C-A

Variant names:

• chr19-35826654-C-A
• rs77309273
• NM_004646.4:c.3595-9G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.3595-9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,613,580 control chromosomes in the GnomAD database, including 2,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (180 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1894 hom.)
• Consequence: NPHS1 NM_004646.4 intron
• Scores: Splicing: ADA: 0.00003676
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.301
• 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]

NPHS1 Gene-Disease associations (from GenCC):

• congenital nephrotic syndrome, Finnish type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35826654-C-A is Benign according to our data. Variant chr19-35826654-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0531 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.3595-9G>T		intron	N/A	NP_004637.1	O60500-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.3595-9G>T		intron	N/A	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.3535-9G>T		intron	N/A	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.3475-9G>T		intron	N/A	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.0397 AC: 6040 AN: 152034 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.00771

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0417 AC: 10382 AN: 249222 AF XY: 0.0420

Gnomad AFR exome AF: 0.00824

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0480

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0418

GnomAD4 exome AF: 0.0459 AC: 67018 AN: 1461428 Hom.: 1894 Cov.: 31 AF XY: 0.0458 AC XY: 33273 AN XY: 727008

African (AFR) AF: 0.00682 AC: 228 AN: 33454

American (AMR) AF: 0.0213 AC: 954 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1276 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.0135 AC: 1165 AN: 86242

European-Finnish (FIN) AF: 0.107 AC: 5719 AN: 53396

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5754

European-Non Finnish (NFE) AF: 0.0497 AC: 55218 AN: 1111672

Other (OTH) AF: 0.0392 AC: 2369 AN: 60370

GnomAD4 genome AF: 0.0397 AC: 6038 AN: 152152 Hom.: 180 Cov.: 32 AF XY: 0.0417 AC XY: 3099 AN XY: 74388

African (AFR) AF: 0.00768 AC: 319 AN: 41514

American (AMR) AF: 0.0277 AC: 424 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4826

European-Finnish (FIN) AF: 0.113 AC: 1189 AN: 10562

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0546 AC: 3713 AN: 68000

Other (OTH) AF: 0.0340 AC: 72 AN: 2116

Alfa AF: 0.0402 Hom.: 95

Bravo AF: 0.0315

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Finnish congenital nephrotic syndrome (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	-0.82
CADD	Benign	6.0
DANN	Benign	0.58
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0
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: rs77309273; hg19: chr19-36317556;