19-35825976-C-T

Variant names:

• chr19-35825976-C-T
• rs71354105
• NM_004646.4:c.*538G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004646.4(NPHS1):​c.*538G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 152,568 control chromosomes in the GnomAD database, including 536 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.073 (530 hom., cov: 32)
  • Exomes 𝑓: 0.089 (6 hom.)
• Consequence: NPHS1 NM_004646.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• 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: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.*538G>A		3_prime_UTR_variant	Exon 29 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.*538G>A		3_prime_UTR_variant	Exon 29 of 29	1	NM_004646.4	ENSP00000368190.4

Frequencies

GnomAD3 genomes AF: 0.0733 AC: 11135 AN: 151936 Hom.: 530 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0773

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0758

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0869

GnomAD4 exome AF: 0.0895 AC: 46 AN: 514 Hom.: 6 Cov.: 0 AF XY: 0.0899 AC XY: 25 AN XY: 278

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.0481 AC: 5 AN: 104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.146 AC: 7 AN: 48

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0982 AC: 32 AN: 326

Other (OTH) AF: 0.111 AC: 2 AN: 18

GnomAD4 genome AF: 0.0732 AC: 11136 AN: 152054 Hom.: 530 Cov.: 32 AF XY: 0.0730 AC XY: 5423 AN XY: 74308

African (AFR) AF: 0.0205 AC: 850 AN: 41490

American (AMR) AF: 0.0772 AC: 1179 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 393 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.104 AC: 500 AN: 4820

European-Finnish (FIN) AF: 0.0758 AC: 800 AN: 10554

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7066 AN: 67972

Other (OTH) AF: 0.0859 AC: 181 AN: 2106

Alfa AF: 0.0264 Hom.: 15

Bravo AF: 0.0682

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital nephrotic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.53
DANN	Benign	0.87
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs71354105; hg19: chr19-36316878;