rs148755697

Variant names:

• chr19-35825985-G-A
• rs148755697
• NM_004646.4:c.*529C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-35825985-G-A
• chr19-35825985-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_004646.4(NPHS1):​c.*529C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 152,194 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.023 (54 hom., cov: 32)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: NPHS1 NM_004646.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.56
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, ClinGen, Orphanet
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3508/151718) while in subpopulation NFE AF = 0.0373 (2535/67924). AF 95% confidence interval is 0.0361. There are 54 homozygotes in GnomAd4. There are 1635 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 54 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.*529C>T		3_prime_UTR	Exon 29 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.*529C>T		3_prime_UTR	Exon 29 of 29	ENSP00000368190.4	O60500-1
	NPHS1	ENST00000869106.1		c.*529C>T		3_prime_UTR	Exon 29 of 29	ENSP00000539165.1
	NPHS1	ENST00000869107.1		c.*529C>T		3_prime_UTR	Exon 27 of 27	ENSP00000539166.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3508 AN: 151600 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00499

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0373

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.0210 AC: 10 AN: 476 Hom.: 0 Cov.: 0 AF XY: 0.0221 AC XY: 6 AN XY: 272

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.0288 AC: 3 AN: 104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.0263 AC: 1 AN: 38

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0205 AC: 6 AN: 292

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.0231 AC: 3508 AN: 151718 Hom.: 54 Cov.: 32 AF XY: 0.0221 AC XY: 1635 AN XY: 74144

African (AFR) AF: 0.00662 AC: 274 AN: 41360

American (AMR) AF: 0.0153 AC: 233 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00499 AC: 24 AN: 4806

European-Finnish (FIN) AF: 0.0308 AC: 324 AN: 10522

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

European-Non Finnish (NFE) AF: 0.0373 AC: 2535 AN: 67924

Other (OTH) AF: 0.0123 AC: 26 AN: 2106

Alfa AF: 0.0106 Hom.: 1

Bravo AF: 0.0214

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital nephrotic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.69
PhyloP100		-2.6
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: rs148755697; hg19: chr19-36316887;