rs116606479

Variant names:

• chr1-5874953-C-T
• rs116606479
• NM_015102.5:c.2965G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BS1_Supporting

The NM_015102.5(NPHP4):​c.2965G>A​(p.Glu989Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,613,458 control chromosomes in the GnomAD database, including 1 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 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 5.87

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36386117).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000617 (94/152240) while in subpopulation AFR AF= 0.00168 (70/41548). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2965G>A	p.Glu989Lys	missense_variant	Exon 21 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2965G>A	p.Glu989Lys	missense_variant	Exon 21 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1866G>A		non_coding_transcript_exon_variant	Exon 18 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*776G>A		non_coding_transcript_exon_variant	Exon 24 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*1866G>A		3_prime_UTR_variant	Exon 18 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*776G>A		3_prime_UTR_variant	Exon 24 of 33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000430 AC: 107 AN: 248728 Hom.: 0 AF XY: 0.000415 AC XY: 56 AN XY: 134998

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000261 AC: 381 AN: 1461218 Hom.: 1 Cov.: 33 AF XY: 0.000275 AC XY: 200 AN XY: 726884

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000777

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74446

Gnomad4 AFR AF: 0.00168

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.000831

ESP6500AA AF: 0.00162 AC: 7

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with a clinical diagnosis of Senior-Loken syndrome, in cis with another missense allele; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32865313) -

Mar 15, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHP4 p.Glu989Lys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs116606479), ClinVar (classified as a VUS by Invitae, EGL Genetics, GeneDx and Illumina), and in LOVD 3.0 (variant is listed as likely benign). The variant was also identified in control databases in 125 of 280094 chromosomes at a frequency of 0.000446 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24192 chromosomes (freq: 0.002067), Other in 8 of 7136 chromosomes (freq: 0.001121), South Asian in 17 of 30602 chromosomes (freq: 0.000556), Latino in 17 of 35368 chromosomes (freq: 0.000481), European (non-Finnish) in 31 of 128312 chromosomes (freq: 0.000242) and East Asian in 2 of 19532 chromosomes (freq: 0.000102), but not in the Ashkenazi Jewish, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu989 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nephronophthisis 4 Uncertain:2

Jan 15, 2022

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Nephronophthisis Uncertain:1 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

NPHP4-related disorder Uncertain:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NPHP4 c.2965G>A variant is predicted to result in the amino acid substitution p.Glu989Lys. This variant along with two other NPHP4 variants (c.2951C>T, p.Thr984Met and c.2203C>T, p.Arg735Trp) were reported in an individual with Senior–Løken syndrome (Sallum et al. 2020. PubMed ID: 32865313). This variant was also reported as uncertain significance with c.2203C>T (p.Arg735Trp) in individuals with chronic kidney disease and nephronophthisis (Al-Hamed et al. 2022. PubMed ID: 36177613; Tables S2 and S3, König et al. 2022. PubMed ID: 36090483). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may possibly be benign, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Senior-Loken syndrome 4 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.9	M
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.95
MPC		0.41
ClinPred		0.036	T
GERP RS		5.0
Varity_R		0.40
gMVP		0.96

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: rs116606479; hg19: chr1-5935013;