chr19-35851310-C-T

Variant names:

• chr19-35851310-C-T
• rs3814995
• NM_004646.4:c.349G>A

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.349G>A​(p.Glu117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,613,534 control chromosomes in the GnomAD database, including 81,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6489 hom., cov: 31)
  • Exomes 𝑓: 0.31 (75013 hom.)
• Consequence: NPHS1 NM_004646.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.48

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]

KIRREL2 (HGNC:18816): (kirre like nephrin family adhesion molecule 2) This gene encodes a type I transmembrane protein and member of the immunoglobulin superfamily of cell adhesion molecules. The encoded protein localizes to adherens junctions in pancreatic beta cells and regulates insulin secretion. Autoantibodies against the encoded protein have been detected in serum from patients with type 1 diabetes. This gene may also play a role in glomerular development and decreased expression of this gene has been observed in human glomerular diseases. This gene and the related opposite-strand gene nephrin (GeneID: 527362) are regulated by a bidirectional promoter. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a domain Ig-like C2-type 1 (size 103) in uniprot entity NPHN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004646.4
• BP4: Computational evidence support a benign effect (MetaRNN=1.4799833E-4).
• BP6: Variant 19-35851310-C-T is Benign according to our data. Variant chr19-35851310-C-T is described in ClinVar as [Benign]. Clinvar id is 259500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35851310-C-T is described in Lovd as [Benign]. Variant chr19-35851310-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.349G>A	p.Glu117Lys	missense_variant	Exon 3 of 29	ENST00000378910.10	NP_004637.1
KIRREL2	XM_011527362.2	c.-597C>T		upstream_gene_variant			XP_011525664.1
KIRREL2	XM_011527363.2	c.-588C>T		upstream_gene_variant			XP_011525665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.349G>A	p.Glu117Lys	missense_variant	Exon 3 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.349G>A	p.Glu117Lys	missense_variant	Exon 3 of 28	5		ENSP00000343634.5

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39879 AN: 151938 Hom.: 6490 Cov.: 31

Gnomad AFR AF: 0.0864

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.620

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.324 AC: 81058 AN: 249994 Hom.: 14699 AF XY: 0.318 AC XY: 43000 AN XY: 135268

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.611

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.358

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.308

GnomAD4 exome AF: 0.313 AC: 457173 AN: 1461478 Hom.: 75013 Cov.: 54 AF XY: 0.311 AC XY: 226220 AN XY: 727008

Gnomad4 AFR exome AF: 0.0745

Gnomad4 AMR exome AF: 0.410

Gnomad4 ASJ exome AF: 0.263

Gnomad4 EAS exome AF: 0.606

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.305

GnomAD4 genome AF: 0.262 AC: 39876 AN: 152056 Hom.: 6489 Cov.: 31 AF XY: 0.268 AC XY: 19898 AN XY: 74312

Gnomad4 AFR AF: 0.0862

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.293

Alfa AF: 0.293 Hom.: 9316

Bravo AF: 0.259

TwinsUK AF: 0.321 AC: 1191

ALSPAC AF: 0.307 AC: 1185

ESP6500AA AF: 0.0919 AC: 405

ESP6500EA AF: 0.306 AC: 2628

ExAC AF: 0.311 AC: 37806

Asia WGS AF: 0.378 AC: 1313 AN: 3478

EpiCase AF: 0.304

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Finnish congenital nephrotic syndrome Benign:5

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The NPHS1 c.349G>A (p.Glu117Lys) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 37468/119026 control chromosomes (6569 homozygotes) at a frequency of 0.3147884, which is approximately 94 times the estimated maximal expected allele frequency of a pathogenic NPHS1 variant (0.0033541), evidence that this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -

not specified Benign:3

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 69% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 64. Only high quality variants are reported. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital nephrotic syndrome Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.00015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.096	T;T
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.49
MPC		0.62
ClinPred		0.023	T
GERP RS		5.9
Varity_R		0.33
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3814995; hg19: chr19-36342212; COSMIC: COSV62287878; COSMIC: COSV62287878;