chr19-35843583-G-A

Variant names:

• chr19-35843583-G-A
• rs2073901
• NM_004646.4:c.2223C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.2223C>T​(p.Thr741Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,614,032 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (145 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.687
• Publications: 7 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 -16 ACMG points.

• BP6: Variant 19-35843583-G-A is Benign according to our data. Variant chr19-35843583-G-A is described in ClinVar as Benign. ClinVar VariationId is 259488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0519 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.2223C>T	p.Thr741Thr	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.2223C>T	p.Thr741Thr	synonymous	Exon 17 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000585400.1	TSL:1	n.914C>T		non_coding_transcript_exon	Exon 3 of 3
	NPHS1	ENST00000869106.1		c.2163C>T	p.Thr721Thr	synonymous	Exon 17 of 29	ENSP00000539165.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 783 AN: 152224 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00813

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00673 AC: 1693 AN: 251440 AF XY: 0.00675

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.0580

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00342 AC: 5000 AN: 1461690 Hom.: 145 Cov.: 31 AF XY: 0.00361 AC XY: 2627 AN XY: 727136

African (AFR) AF: 0.00860 AC: 288 AN: 33474

American (AMR) AF: 0.000671 AC: 30 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00746 AC: 195 AN: 26134

East Asian (EAS) AF: 0.0733 AC: 2909 AN: 39680

South Asian (SAS) AF: 0.0108 AC: 934 AN: 86236

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53400

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.000323 AC: 359 AN: 1111894

Other (OTH) AF: 0.00417 AC: 252 AN: 60386

GnomAD4 genome AF: 0.00513 AC: 781 AN: 152342 Hom.: 11 Cov.: 32 AF XY: 0.00515 AC XY: 384 AN XY: 74492

African (AFR) AF: 0.00810 AC: 337 AN: 41582

American (AMR) AF: 0.00131 AC: 20 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.0572 AC: 296 AN: 5172

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4832

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00297 Hom.: 2

Bravo AF: 0.00530

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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	-0.41
CADD	Benign	5.6
DANN	Benign	0.69
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 10

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

Other links and lift over

dbSNP: rs2073901; hg19: chr19-36334485; COSMIC: COSV62286562; COSMIC: COSV62286562;