19-35849107-G-A

Variant names:

• chr19-35849107-G-A
• rs113825926
• NM_004646.4:c.881C>T
• NPHS1 p.Thr294Ile

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004646.4(NPHS1):​c.881C>T​(p.Thr294Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,609,588 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T294T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0083 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (130 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0780
• 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, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 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, 3 uncertain in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0051461756).
• BP6: Variant 19-35849107-G-A is Benign according to our data. Variant chr19-35849107-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00835 (1272/152352) while in subpopulation NFE AF = 0.0137 (930/68024). AF 95% confidence interval is 0.0129. There are 8 homozygotes in GnomAd4. There are 603 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.881C>T	p.Thr294Ile	missense	Exon 8 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.881C>T	p.Thr294Ile	missense	Exon 8 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.881C>T	p.Thr294Ile	missense	Exon 8 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.881C>T	p.Thr294Ile	missense	Exon 8 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1271 AN: 152234 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00630

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00774 AC: 1897 AN: 245030 AF XY: 0.00803

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00856

GnomAD4 exome AF: 0.0112 AC: 16375 AN: 1457236 Hom.: 130 Cov.: 32 AF XY: 0.0112 AC XY: 8120 AN XY: 725134

African (AFR) AF: 0.00376 AC: 126 AN: 33472

American (AMR) AF: 0.00331 AC: 148 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26128

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

South Asian (SAS) AF: 0.00393 AC: 339 AN: 86248

European-Finnish (FIN) AF: 0.00697 AC: 341 AN: 48952

Middle Eastern (MID) AF: 0.00475 AC: 27 AN: 5686

European-Non Finnish (NFE) AF: 0.0134 AC: 14903 AN: 1111976

Other (OTH) AF: 0.00766 AC: 462 AN: 60352

GnomAD4 genome AF: 0.00835 AC: 1272 AN: 152352 Hom.: 8 Cov.: 32 AF XY: 0.00809 AC XY: 603 AN XY: 74502

African (AFR) AF: 0.00368 AC: 153 AN: 41580

American (AMR) AF: 0.00510 AC: 78 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4834

European-Finnish (FIN) AF: 0.00630 AC: 67 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 930 AN: 68024

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.0120 Hom.: 41

Bravo AF: 0.00794

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.8
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.078
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.071
Sift	Benign	0.060	T
Sift4G	Benign	0.28	T
Varity_R		0.084
gMVP		0.43
Mutation Taster		=98/2	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113825926;

hg19: chr19-36340009;

COSMIC: COSV62286333;

COSMIC: COSV62286333;