19-35831368-C-T

Variant names:

• chr19-35831368-C-T
• rs2071327
• NM_004646.4:c.3315G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.3315G>A​(p.Ser1105Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,270 control chromosomes in the GnomAD database, including 122,372 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. S1105S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (9723 hom., cov: 30)
  • Exomes 𝑓: 0.39 (112649 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.20
• Publications: 24 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 -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-35831368-C-T is Benign according to our data. Variant chr19-35831368-C-T is described in ClinVar as Benign. ClinVar VariationId is 259497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 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.3315G>A	p.Ser1105Ser	synonymous	Exon 26 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.3315G>A	p.Ser1105Ser	synonymous	Exon 26 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.3255G>A	p.Ser1085Ser	synonymous	Exon 26 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.3195G>A	p.Ser1065Ser	synonymous	Exon 25 of 28	ENSP00000343634.5	O60500-2

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49111 AN: 151728 Hom.: 9718 Cov.: 30

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.351

GnomAD2 exomes AF: 0.400 AC: 100518 AN: 251432 AF XY: 0.402

Gnomad AFR exome AF: 0.0995

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.648

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.373

GnomAD4 exome AF: 0.385 AC: 563048 AN: 1461424 Hom.: 112649 Cov.: 43 AF XY: 0.387 AC XY: 281213 AN XY: 727048

African (AFR) AF: 0.0880 AC: 2947 AN: 33474

American (AMR) AF: 0.417 AC: 18632 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9132 AN: 26134

East Asian (EAS) AF: 0.655 AC: 25986 AN: 39698

South Asian (SAS) AF: 0.405 AC: 34943 AN: 86252

European-Finnish (FIN) AF: 0.483 AC: 25767 AN: 53402

Middle Eastern (MID) AF: 0.275 AC: 1585 AN: 5766

European-Non Finnish (NFE) AF: 0.379 AC: 421247 AN: 1111590

Other (OTH) AF: 0.378 AC: 22809 AN: 60384

GnomAD4 genome AF: 0.323 AC: 49121 AN: 151846 Hom.: 9723 Cov.: 30 AF XY: 0.332 AC XY: 24645 AN XY: 74164

African (AFR) AF: 0.102 AC: 4234 AN: 41448

American (AMR) AF: 0.385 AC: 5867 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1196 AN: 3466

East Asian (EAS) AF: 0.662 AC: 3395 AN: 5126

South Asian (SAS) AF: 0.428 AC: 2059 AN: 4812

European-Finnish (FIN) AF: 0.488 AC: 5146 AN: 10538

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 25996 AN: 67908

Other (OTH) AF: 0.357 AC: 749 AN: 2098

Alfa AF: 0.349 Hom.: 15485

Bravo AF: 0.308

Asia WGS AF: 0.546 AC: 1896 AN: 3478

EpiCase AF: 0.370

EpiControl AF: 0.366

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Finnish congenital nephrotic syndrome (3)
-	-	2	not provided (2)
-	-	1	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.42
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: -2

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

Other links and lift over

dbSNP: rs2071327; hg19: chr19-36322270; COSMIC: COSV107439337;