rs34736717

Positions:

• chr19-35839375-C-G
• chr19-35839375-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004646.4(NPHS1):​c.2971G>C​(p.Val991Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,614,086 control chromosomes in the GnomAD database, including 762 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (405 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (357 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.997

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain Fibronectin type-III (size 95) in uniprot entity NPHN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023097098).
• BP6: Variant 19-35839375-C-G is Benign according to our data. Variant chr19-35839375-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 259493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.2971G>C	p.Val991Leu	missense_variant	22/29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.2971G>C	p.Val991Leu	missense_variant	22/29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.2971G>C	p.Val991Leu	missense_variant	22/28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5848 AN: 152092 Hom.: 396 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0216

GnomAD3 exomes AF: 0.0105 AC: 2648 AN: 251470 Hom.: 181 AF XY: 0.00742 AC XY: 1008 AN XY: 135918

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.00327

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00418 AC: 6111 AN: 1461876 Hom.: 357 Cov.: 32 AF XY: 0.00358 AC XY: 2605 AN XY: 727242

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.00754

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.0387 AC: 5890 AN: 152210 Hom.: 405 Cov.: 32 AF XY: 0.0371 AC XY: 2763 AN XY: 74426

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.00278 Hom.: 7

Bravo AF: 0.0445

ESP6500AA AF: 0.137 AC: 602

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0129 AC: 1561

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2018	Variant summary: NPHS1 c.2971G>C (p.Val991Leu) results in a conservative amino acid change located in the Fibronectin type III domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.013 in 277180 control chromosomes, predominantly within the African subpopulation at a frequency of 0.14 in the gnomAD database, including 231 homozygotes. The observed variant frequency within African control individuals is approximately 42 fold above the estimated maximal expected allele frequency for a pathogenic variant in NPHS1 causing Nephrotic Syndrome, Type 1 phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant has been cited in the literature as a polymorphism (e.g., Machuca_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 16, 2022

- -

Finnish congenital nephrotic syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Congenital nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	14
DANN	Benign	0.28
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;L
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.084
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.47		Loss of glycosylation at T996 (P = 0.227);Loss of glycosylation at T996 (P = 0.227);
MPC		0.10
ClinPred		0.0099	T
GERP RS		1.1
Varity_R		0.028
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs34736717; hg19: chr19-36330277;