rs392702

Variant names:

• chr19-35848161-G-A
• rs392702
• NM_004646.4:c.1320C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004646.4(NPHS1):​c.1320C>T​(p.Pro440Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0431 in 1,613,988 control chromosomes in the GnomAD database, including 2,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1072 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1747 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.40
• Publications: 10 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-35848161-G-A is Benign according to our data. Variant chr19-35848161-G-A is described in ClinVar as Benign. ClinVar VariationId is 259484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 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.1320C>T	p.Pro440Pro	synonymous	Exon 11 of 29	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.1320C>T	p.Pro440Pro	synonymous	Exon 11 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.1320C>T	p.Pro440Pro	synonymous	Exon 11 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.1320C>T	p.Pro440Pro	synonymous	Exon 11 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.0852 AC: 12957 AN: 152136 Hom.: 1070 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.0462

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0455 AC: 11400 AN: 250822 AF XY: 0.0433

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0467

Gnomad EAS exome AF: 0.00561

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0387 AC: 56572 AN: 1461734 Hom.: 1747 Cov.: 31 AF XY: 0.0384 AC XY: 27906 AN XY: 727174

African (AFR) AF: 0.217 AC: 7277 AN: 33480

American (AMR) AF: 0.0272 AC: 1217 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1212 AN: 26136

East Asian (EAS) AF: 0.00390 AC: 155 AN: 39698

South Asian (SAS) AF: 0.0499 AC: 4302 AN: 86256

European-Finnish (FIN) AF: 0.0428 AC: 2283 AN: 53288

Middle Eastern (MID) AF: 0.0402 AC: 232 AN: 5768

European-Non Finnish (NFE) AF: 0.0334 AC: 37143 AN: 1111992

Other (OTH) AF: 0.0456 AC: 2751 AN: 60392

GnomAD4 genome AF: 0.0853 AC: 12982 AN: 152254 Hom.: 1072 Cov.: 32 AF XY: 0.0839 AC XY: 6247 AN XY: 74456

African (AFR) AF: 0.216 AC: 8974 AN: 41504

American (AMR) AF: 0.0481 AC: 736 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 149 AN: 3468

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5188

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4824

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10620

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0327 AC: 2224 AN: 68030

Other (OTH) AF: 0.0766 AC: 162 AN: 2116

Alfa AF: 0.0508 Hom.: 619

Bravo AF: 0.0913

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0315

EpiControl AF: 0.0375

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Finnish congenital nephrotic syndrome (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.5
DANN	Benign	0.71
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs392702; hg19: chr19-36339063;