rs139203183

Variant names:

• chr1-5863416-G-A
• rs139203183
• ENST00000460696.1:n.3362C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The ENST00000460696.1(NPHP4):​n.3362C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00095 in 1,594,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (0 hom.)
• Consequence: NPHP4 ENST00000460696.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 0.00002664
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.251
• Publications: 0 publications found

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]

NPHP4 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-5863416-G-A is Benign according to our data. Variant chr1-5863416-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260560.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000638 (95/148836) while in subpopulation NFE AF = 0.00124 (83/66736). AF 95% confidence interval is 0.00103. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.4141-11C>T		intron_variant	Intron 29 of 29	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.4141-11C>T		intron_variant	Intron 29 of 29	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*3042-11C>T		intron_variant	Intron 26 of 26	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*1952-11C>T		intron_variant	Intron 32 of 32	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.000639 AC: 95 AN: 148716 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000996

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.000876

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000285

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00124

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000611 AC: 150 AN: 245642 AF XY: 0.000674

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.000667

GnomAD4 exome AF: 0.000982 AC: 1419 AN: 1445578 Hom.: 0 Cov.: 32 AF XY: 0.000951 AC XY: 683 AN XY: 718108

African (AFR) AF: 0.0000602 AC: 2 AN: 33218

American (AMR) AF: 0.0000230 AC: 1 AN: 43398

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 30 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39090

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83978

European-Finnish (FIN) AF: 0.0000754 AC: 4 AN: 53018

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5698

European-Non Finnish (NFE) AF: 0.00122 AC: 1341 AN: 1101724

Other (OTH) AF: 0.000637 AC: 38 AN: 59612

GnomAD4 genome AF: 0.000638 AC: 95 AN: 148836 Hom.: 0 Cov.: 33 AF XY: 0.000481 AC XY: 35 AN XY: 72714

African (AFR) AF: 0.0000993 AC: 4 AN: 40282

American (AMR) AF: 0.000133 AC: 2 AN: 15038

Ashkenazi Jewish (ASJ) AF: 0.000876 AC: 3 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4706

European-Finnish (FIN) AF: 0.000285 AC: 3 AN: 10516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00124 AC: 83 AN: 66736

Other (OTH) AF: 0.00 AC: 0 AN: 2042

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000570

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Senior-Loken syndrome 4 Uncertain:1

Jan 13, 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 4 Uncertain:1

Jan 13, 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. -

NPHP4-related disorder Benign:1

Sep 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nephronophthisis Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.78
PhyloP100		0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs139203183; hg19: chr1-5923476;