rs76131336

Variant names:

• chr19-35845358-G-A
• rs76131336
• NM_004646.4:c.1930+10C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004646.4(NPHS1):​c.1930+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,614,158 control chromosomes in the GnomAD database, including 192 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 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (176 hom.)
• Consequence: NPHS1 NM_004646.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.139
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-35845358-G-A is Benign according to our data. Variant chr19-35845358-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259485.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00996 (1517/152378) while in subpopulation NFE AF = 0.0159 (1080/68038). AF 95% confidence interval is 0.0151. There are 16 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.1930+10C>T		intron	N/A	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.1930+10C>T		intron	N/A	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000585400.1	TSL:1	n.112+41C>T		intron	N/A
	NPHS1	ENST00000869106.1		c.1870+10C>T		intron	N/A	ENSP00000539165.1

Frequencies

GnomAD3 genomes AF: 0.00996 AC: 1516 AN: 152260 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00943 AC: 2369 AN: 251138 AF XY: 0.00936

Gnomad AFR exome AF: 0.00259

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0139 AC: 20326 AN: 1461780 Hom.: 176 Cov.: 34 AF XY: 0.0137 AC XY: 9928 AN XY: 727194

African (AFR) AF: 0.00218 AC: 73 AN: 33480

American (AMR) AF: 0.00626 AC: 280 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 552 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00342 AC: 295 AN: 86250

European-Finnish (FIN) AF: 0.00296 AC: 158 AN: 53420

Middle Eastern (MID) AF: 0.0103 AC: 59 AN: 5732

European-Non Finnish (NFE) AF: 0.0163 AC: 18157 AN: 1111960

Other (OTH) AF: 0.0124 AC: 751 AN: 60380

GnomAD4 genome AF: 0.00996 AC: 1517 AN: 152378 Hom.: 16 Cov.: 32 AF XY: 0.00910 AC XY: 678 AN XY: 74514

African (AFR) AF: 0.00308 AC: 128 AN: 41600

American (AMR) AF: 0.00927 AC: 142 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4834

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0159 AC: 1080 AN: 68038

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0132 Hom.: 8

Bravo AF: 0.0102

Asia WGS AF: 0.00202 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Atypical hemolytic-uremic syndrome (1)
-	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	-0.75
CADD	Benign	11
DANN	Benign	0.89
PhyloP100		0.14
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: rs76131336; hg19: chr19-36336260;