NM_015102.5:c.271T>C

Variant names:

• chr1-5978278-A-G
• rs201065230
• NM_015102.5:c.271T>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

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:10 B:2
• 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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04121715).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00105 (160/152072) while in subpopulation NFE AF= 0.00201 (137/68012). AF 95% confidence interval is 0.00174. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.271T>C	p.Phe91Leu	missense_variant	Exon 3 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.271T>C	p.Phe91Leu	missense_variant	Exon 3 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.271T>C		non_coding_transcript_exon_variant	Exon 3 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.271T>C		non_coding_transcript_exon_variant	Exon 3 of 33	2		ENSP00000423747.1

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:10 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5 Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP4: BS2 -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in published literature as heterozygous in an individual with mesocardia and laterality defects (PMID: 22550138); 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 (PMID: 29974258); 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 (PMID: 15776426, 21068128); 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 (PMID: 21546380); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23188109, 21068128, 36090483, 32483926, 22550138, 29974258, 21546380, 15776426) -

not specified Uncertain:1

Mar 30, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

NPHP4-related disorder Uncertain:1

May 10, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHP4 c.271T>C variant is predicted to result in the amino acid substitution p.Phe91Leu. This variant has been reported in the heterozygous state in at least two different individuals with nephronophthisis; however, a second NPHP4 variant was not detected in these individuals (Hoefele et al. 2005. PubMed ID: 15776426; Otto et al. 2010. PubMed ID: 21068128). This variant was also described in a large cohort of individuals with retinal or optic nerve disorders (Dineiro et al. 2020. PubMed ID: 32483926, described as a variant of uncertain significance in Table S12) as well as in the compound heterozygous state in an individual with a suspected ciliopathy (Stokman et al. 2018. PubMed ID: 29974258, Table S1). This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Senior-Loken syndrome 4 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. 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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephronophthisis 4 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. 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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
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;