rs34736717

Variant names:

• chr19-35839375-C-G
• rs34736717
• NM_004646.4:c.2971G>C

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V991I) has been classified as Uncertain significance.

• 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
• Publications: 11 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 -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
NPHS1	NM_004646.4	c.2971G>C	p.Val991Leu	missense_variant	Exon 22 of 29	ENST00000378910.10	NP_004637.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHS1	ENST00000378910.10	c.2971G>C	p.Val991Leu	missense_variant	Exon 22 of 29	1	NM_004646.4	ENSP00000368190.4
NPHS1	ENST00000353632.6	c.2971G>C	p.Val991Leu	missense_variant	Exon 22 of 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

GnomAD2 exomes AF: 0.0105 AC: 2648 AN: 251470 AF XY: 0.00742

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 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

African (AFR) AF: 0.143 AC: 4787 AN: 33472

American (AMR) AF: 0.00754 AC: 337 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26136

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

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5768

European-Non Finnish (NFE) AF: 0.000170 AC: 189 AN: 1112002

Other (OTH) AF: 0.00982 AC: 593 AN: 60396

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

African (AFR) AF: 0.134 AC: 5576 AN: 41504

American (AMR) AF: 0.0154 AC: 236 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68012

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Finnish congenital nephrotic syndrome Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Congenital nephrotic syndrome Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.0
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs34736717; hg19: chr19-36330277;