19-35831116-G-T

Variant names:

• chr19-35831116-G-T
• rs143092783
• NM_004646.4:c.3418C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004646.4(NPHS1):​c.3418C>A​(p.Arg1140Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,613,946 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. R1140H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (4 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.89
• Publications: 9 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 (MetaRNN=0.009340763).
• BP6: Variant 19-35831116-G-T is Benign according to our data. Variant chr19-35831116-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00374 (569/152212) while in subpopulation AFR AF = 0.0129 (535/41546). AF 95% confidence interval is 0.012. There are 6 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.3418C>A	p.Arg1140Ser	missense	Exon 27 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.3418C>A	p.Arg1140Ser	missense	Exon 27 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.3358C>A	p.Arg1120Ser	missense	Exon 27 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.3298C>A	p.Arg1100Ser	missense	Exon 26 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 568 AN: 152094 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000983 AC: 247 AN: 251274 AF XY: 0.000736

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000401 AC: 586 AN: 1461734 Hom.: 4 Cov.: 34 AF XY: 0.000355 AC XY: 258 AN XY: 727182

African (AFR) AF: 0.0119 AC: 400 AN: 33478

American (AMR) AF: 0.000783 AC: 35 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5716

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1111994

Other (OTH) AF: 0.00101 AC: 61 AN: 60384

GnomAD4 genome AF: 0.00374 AC: 569 AN: 152212 Hom.: 6 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74428

African (AFR) AF: 0.0129 AC: 535 AN: 41546

American (AMR) AF: 0.00131 AC: 20 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.000287 Hom.: 0

Bravo AF: 0.00416

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	Finnish congenital nephrotic syndrome (4)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.084
Sift	Benign	0.079	T
Sift4G	Uncertain	0.044	D
Polyphen		0.010	B
Vest4		0.35
MVP		0.72
MPC		0.12
ClinPred		0.018	T
GERP RS		1.6
Varity_R		0.072
gMVP		0.37
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs143092783; hg19: chr19-36322018; COSMIC: COSV62286682;