rs437168

Variant names:

• chr19-35843517-G-A
• rs437168
• NM_004646.4:c.2289C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-35843517-G-A
• chr19-35843517-G-C

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.2289C>T​(p.Val763Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0635 in 1,613,890 control chromosomes in the GnomAD database, including 10,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V763V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (4540 hom., cov: 32)
  • Exomes 𝑓: 0.053 (5666 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.07
• Publications: 28 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=-0.76).
• BP6: Variant 19-35843517-G-A is Benign according to our data. Variant chr19-35843517-G-A is described in ClinVar as Benign. ClinVar VariationId is 259489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 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.2289C>T	p.Val763Val	synonymous	Exon 17 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.2289C>T	p.Val763Val	synonymous	Exon 17 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000585400.1	TSL:1	n.980C>T		non_coding_transcript_exon	Exon 3 of 3
	NPHS1	ENST00000869106.1		c.2229C>T	p.Val743Val	synonymous	Exon 17 of 29	ENSP00000539165.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24457 AN: 152026 Hom.: 4509 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0771

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0349

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.0788 AC: 19829 AN: 251486 AF XY: 0.0717

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.0728

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0359

Gnomad OTH exome AF: 0.0594

GnomAD4 exome AF: 0.0533 AC: 77898 AN: 1461746 Hom.: 5666 Cov.: 32 AF XY: 0.0523 AC XY: 38011 AN XY: 727186

African (AFR) AF: 0.467 AC: 15641 AN: 33470

American (AMR) AF: 0.0431 AC: 1927 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 1869 AN: 26132

East Asian (EAS) AF: 0.168 AC: 6667 AN: 39694

South Asian (SAS) AF: 0.0681 AC: 5877 AN: 86246

European-Finnish (FIN) AF: 0.0431 AC: 2300 AN: 53404

Middle Eastern (MID) AF: 0.0801 AC: 462 AN: 5768

European-Non Finnish (NFE) AF: 0.0348 AC: 38737 AN: 1111922

Other (OTH) AF: 0.0732 AC: 4418 AN: 60388

GnomAD4 genome AF: 0.161 AC: 24533 AN: 152144 Hom.: 4540 Cov.: 32 AF XY: 0.158 AC XY: 11740 AN XY: 74396

African (AFR) AF: 0.455 AC: 18883 AN: 41456

American (AMR) AF: 0.0770 AC: 1177 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3470

East Asian (EAS) AF: 0.151 AC: 783 AN: 5174

South Asian (SAS) AF: 0.0712 AC: 343 AN: 4820

European-Finnish (FIN) AF: 0.0411 AC: 436 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0350 AC: 2377 AN: 68010

Other (OTH) AF: 0.120 AC: 253 AN: 2112

Alfa AF: 0.0671 Hom.: 1677

Bravo AF: 0.178

Asia WGS AF: 0.121 AC: 422 AN: 3478

EpiCase AF: 0.0349

EpiControl AF: 0.0414

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Finnish congenital nephrotic syndrome (5)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.2
DANN	Benign	0.63
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs437168; hg19: chr19-36334419; COSMIC: COSV62286972; COSMIC: COSV62286972;