rs201065230

chr1-5978278-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015102.5(NPHP4):c.271T>C(p.Phe91Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00149 in 1,606,598 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 3.73

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04121715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.271T>C	p.Phe91Leu	missense_variant	3/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.271T>C	p.Phe91Leu	missense_variant	3/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152072 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000901 AC: 214 AN: 237496 Hom.: 0 AF XY: 0.000890 AC XY: 115 AN XY: 129238

Gnomad AFR exome AF: 0.000209

Gnomad AMR exome AF: 0.0000601

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000334

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.000859

GnomAD4 exome AF: 0.00153 AC: 2230 AN: 1454526 Hom.: 4 Cov.: 31 AF XY: 0.00149 AC XY: 1074 AN XY: 722960

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000537

Gnomad4 NFE exome AF: 0.00193

Gnomad4 OTH exome AF: 0.000865

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152072 Hom.: 0 Cov.: 29 AF XY: 0.000996 AC XY: 74 AN XY: 74276

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00201

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000895

ESP6500AA AF: 0.000484 AC: 2

ESP6500EA AF: 0.00167 AC: 14

ExAC AF: 0.000929 AC: 112

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2021	Published functional studies demonstrate a damaging effect: p.F91L (described as p.F83L) failed to rescue the foraging defect and affected localization of NPHP4 in C. elegans, and was concluded to be a hypomorphic variant (Masyukova et al., 2011); Reported in published literature as heterozygous in an individual with mesocardia and laterality defects (French et al., 2012); Reported in published literature as heterozygous in a family with nephronophthisis and retinitis pigmentosa and in unrelated individuals with nephronophthisis; however, a second NPHP4 variant was not identified for these individuals (Hoefele et al., 2005; Otto et al., 2011); Identified in the heterozygous state via multi-gene panel testing in a patient with nephronophthisis who was also found to have a second heterozygous missense variant, but phase was unknown (Stokman et al., 2018); This variant is associated with the following publications: (PMID: 21546380, 22550138, 23188109, 29974258, 21068128, 15776426) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2017

The p.Phe91Leu (NM_015102.3 c.271T>C) variant in NPHP4 has been reported in 2 Ca ucasian individuals with Nephronophthisis and 1 individual with mesocardia, thou gh none with a second pathogenic variant on the other allele (Hoefele 2005, Otto 2011, and French 2012). This variant has also been reported in ClinVar (Variati on ID#16995440). This variant has been identified in 0.23% (95/41,774) of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201065230). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Ani mal models in C. elegans suggest that this variant is may lead to partial loss o f function; however, it is unclear how this partial loss of function may lead to disease (Masyukova 2011). In summary, the clinical significance of the p.Phe91L eu variant is uncertain. -

Senior-Loken syndrome 4 Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Nephronophthisis 4 Uncertain:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.21	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.041	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.012	D;D
Polyphen		0.18	B;.
Vest4		0.39
MutPred		0.88		Gain of catalytic residue at F91 (P = 0.0283);Gain of catalytic residue at F91 (P = 0.0283);
MVP		0.92
MPC		0.18
ClinPred		0.054	T
GERP RS		3.6
Varity_R		0.18
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201065230; hg19: chr1-6038338; COSMIC: COSV99071584;