rs33950747

Variant names:

• chr19-35848345-C-T
• rs33950747
• NM_004646.4:c.1223G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP3 BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.1223G>A​(p.Arg408Gln) variant causes a missense change. The variant allele was found at a frequency of 0.061 in 1,614,022 control chromosomes in the GnomAD database, including 3,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R408W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.043 (192 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3254 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 4.07
• Publications: 21 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 -13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_004646.4
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-35848345-C-T is Benign according to our data. Variant chr19-35848345-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0621 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	NM_004646.4	MANE Select	c.1223G>A	p.Arg408Gln	missense	Exon 10 of 29	NP_004637.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.1223G>A	p.Arg408Gln	missense	Exon 10 of 29	ENSP00000368190.4
	NPHS1	ENST00000353632.6	TSL:5	c.1223G>A	p.Arg408Gln	missense	Exon 10 of 28	ENSP00000343634.5
	NPHS1	ENST00000592132.1	TSL:3	n.230G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6601 AN: 152084 Hom.: 192 Cov.: 32

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0887

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0334

GnomAD2 exomes AF: 0.0487 AC: 12251 AN: 251370 AF XY: 0.0483

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0469

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.0897

Gnomad NFE exome AF: 0.0630

Gnomad OTH exome AF: 0.0483

GnomAD4 exome AF: 0.0628 AC: 91858 AN: 1461820 Hom.: 3254 Cov.: 32 AF XY: 0.0614 AC XY: 44639 AN XY: 727218

African (AFR) AF: 0.00944 AC: 316 AN: 33480

American (AMR) AF: 0.0453 AC: 2026 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 651 AN: 26132

East Asian (EAS) AF: 0.000705 AC: 28 AN: 39700

South Asian (SAS) AF: 0.0268 AC: 2310 AN: 86256

European-Finnish (FIN) AF: 0.0873 AC: 4664 AN: 53402

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.0707 AC: 78642 AN: 1111970

Other (OTH) AF: 0.0521 AC: 3147 AN: 60394

GnomAD4 genome AF: 0.0434 AC: 6599 AN: 152202 Hom.: 192 Cov.: 32 AF XY: 0.0431 AC XY: 3206 AN XY: 74408

African (AFR) AF: 0.0108 AC: 449 AN: 41542

American (AMR) AF: 0.0380 AC: 581 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4822

European-Finnish (FIN) AF: 0.0887 AC: 939 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0636 AC: 4328 AN: 67998

Other (OTH) AF: 0.0331 AC: 70 AN: 2116

Alfa AF: 0.0544 Hom.: 857

Bravo AF: 0.0399

TwinsUK AF: 0.0680 AC: 252

ALSPAC AF: 0.0719 AC: 277

ESP6500AA AF: 0.0127 AC: 56

ESP6500EA AF: 0.0634 AC: 545

ExAC AF: 0.0473 AC: 5741

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.0584

EpiControl AF: 0.0535

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Finnish congenital nephrotic syndrome (5)
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	-	1	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.47
Sift	Benign	0.15	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.75
ClinPred		0.028	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.79
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -2

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

Other links and lift over

dbSNP: rs33950747; hg19: chr19-36339247; COSMIC: COSV62289683; COSMIC: COSV62289683;