rs115444936

Variant names:

• chr19-35845788-A-C
• rs115444936
• NM_004646.4:c.1638T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-35845788-A-C
• chr19-35845788-A-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_004646.4(NPHS1):​c.1638T>G​(p.Thr546Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,612,662 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: NPHS1 NM_004646.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.88
• Publications: 3 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-35845788-A-C is Benign according to our data. Variant chr19-35845788-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328869.
• BP7: Synonymous conserved (PhyloP=-1.88 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.1638T>G	p.Thr546Thr	synonymous	Exon 13 of 29	NP_004637.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHS1	ENST00000378910.10	TSL:1 MANE Select	c.1638T>G	p.Thr546Thr	synonymous	Exon 13 of 29	ENSP00000368190.4
	NPHS1	ENST00000869106.1		c.1578T>G	p.Thr526Thr	synonymous	Exon 13 of 29	ENSP00000539165.1
	NPHS1	ENST00000353632.6	TSL:5	c.1638T>G	p.Thr546Thr	synonymous	Exon 13 of 28	ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00167 AC: 418 AN: 250686 AF XY: 0.00184

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000745

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00260 AC: 3796 AN: 1460418 Hom.: 9 Cov.: 34 AF XY: 0.00252 AC XY: 1833 AN XY: 726226

African (AFR) AF: 0.000478 AC: 16 AN: 33442

American (AMR) AF: 0.00170 AC: 76 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000766 AC: 20 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86238

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53364

Middle Eastern (MID) AF: 0.00211 AC: 12 AN: 5692

European-Non Finnish (NFE) AF: 0.00313 AC: 3479 AN: 1110908

Other (OTH) AF: 0.00212 AC: 128 AN: 60308

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.00129 AC XY: 96 AN XY: 74450

African (AFR) AF: 0.000481 AC: 20 AN: 41556

American (AMR) AF: 0.00150 AC: 23 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 67998

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00167

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00320

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	-	Congenital nephrotic syndrome (1)
-	-	1	Finnish congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.4
DANN	Benign	0.66
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs115444936; hg19: chr19-36336690;