rs17472401

chr1-5880183-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):c.2542C>T(p.Arg848Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,640 control chromosomes in the GnomAD database, including 435 homozygotes. In-silico tool predicts 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. R848Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 33)
  • Exomes 𝑓: 0.022 (410 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.48

Genes affected

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007936746).
• BP6: Variant 1-5880183-G-A is Benign according to our data. Variant chr1-5880183-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5880183-G-A is described in Lovd as [Benign]. Variant chr1-5880183-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0156 (2378/152308) while in subpopulation NFE AF= 0.0237 (1614/68022). AF 95% confidence interval is 0.0228. There are 25 homozygotes in gnomad4. There are 1132 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.2542C>T	p.Arg848Trp	missense_variant	19/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.2542C>T	p.Arg848Trp	missense_variant	19/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2378 AN: 152190 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0237

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.0155 AC: 3841 AN: 248334 Hom.: 47 AF XY: 0.0157 AC XY: 2120 AN XY: 134758

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.00418

Gnomad ASJ exome AF: 0.0288

Gnomad EAS exome AF: 0.000502

Gnomad SAS exome AF: 0.00469

Gnomad FIN exome AF: 0.0252

Gnomad NFE exome AF: 0.0228

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0216 AC: 31535 AN: 1461332 Hom.: 410 Cov.: 32 AF XY: 0.0213 AC XY: 15449 AN XY: 726898

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.00466

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00505

Gnomad4 FIN exome AF: 0.0248

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0156 AC: 2378 AN: 152308 Hom.: 25 Cov.: 33 AF XY: 0.0152 AC XY: 1132 AN XY: 74474

Gnomad4 AFR AF: 0.00435

Gnomad4 AMR AF: 0.00803

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0237

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0209 Hom.: 83

Bravo AF: 0.0140

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00363 AC: 15

ESP6500EA AF: 0.0219 AC: 184

ExAC AF: 0.0147 AC: 1785

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2013	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Nephronophthisis 4 Benign:3

Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg848Trp variant in NPHP4 has been identified in 3 individuals with nephronophthisis, segregated with disease in 3 relatives from 1 family (PMID: 12205563), but has also been identified in >2% of European (Finnish) chromosomes and 15 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive nephronophthisis. -
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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NPHP4: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	0.030
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.48
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.020	D;D
Polyphen		1.0	D;.
Vest4		0.58
MPC		0.40
ClinPred		0.015	T
GERP RS		0.78
Varity_R		0.11
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs17472401; hg19: chr1-5940243;