1-5909185-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015102.5(NPHP4):​c.1470C>T​(p.Leu490=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,603,376 control chromosomes in the GnomAD database, including 989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 226 hom., cov: 33)
Exomes 𝑓: 0.027 ( 763 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.09
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
Variant 1-5909185-G-A is Benign according to our data. Variant chr1-5909185-G-A is described in ClinVar as [Benign]. Clinvar id is 260543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5909185-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.09 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP4NM_015102.5 linkuse as main transcriptc.1470C>T p.Leu490= synonymous_variant 12/30 ENST00000378156.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP4ENST00000378156.9 linkuse as main transcriptc.1470C>T p.Leu490= synonymous_variant 12/301 NM_015102.5 P2O75161-1

Frequencies

GnomAD3 genomes
AF:
0.0458
AC:
6971
AN:
152048
Hom.:
226
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.101
Gnomad AMI
AF:
0.0681
Gnomad AMR
AF:
0.0167
Gnomad ASJ
AF:
0.0311
Gnomad EAS
AF:
0.000580
Gnomad SAS
AF:
0.0261
Gnomad FIN
AF:
0.0406
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0249
Gnomad OTH
AF:
0.0483
GnomAD3 exomes
AF:
0.0292
AC:
6689
AN:
229090
Hom.:
159
AF XY:
0.0284
AC XY:
3528
AN XY:
124058
show subpopulations
Gnomad AFR exome
AF:
0.105
Gnomad AMR exome
AF:
0.0106
Gnomad ASJ exome
AF:
0.0316
Gnomad EAS exome
AF:
0.000118
Gnomad SAS exome
AF:
0.0308
Gnomad FIN exome
AF:
0.0412
Gnomad NFE exome
AF:
0.0269
Gnomad OTH exome
AF:
0.0326
GnomAD4 exome
AF:
0.0274
AC:
39767
AN:
1451210
Hom.:
763
Cov.:
32
AF XY:
0.0271
AC XY:
19544
AN XY:
720546
show subpopulations
Gnomad4 AFR exome
AF:
0.107
Gnomad4 AMR exome
AF:
0.0123
Gnomad4 ASJ exome
AF:
0.0332
Gnomad4 EAS exome
AF:
0.0000762
Gnomad4 SAS exome
AF:
0.0320
Gnomad4 FIN exome
AF:
0.0420
Gnomad4 NFE exome
AF:
0.0252
Gnomad4 OTH exome
AF:
0.0296
GnomAD4 genome
AF:
0.0458
AC:
6971
AN:
152166
Hom.:
226
Cov.:
33
AF XY:
0.0455
AC XY:
3385
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.101
Gnomad4 AMR
AF:
0.0167
Gnomad4 ASJ
AF:
0.0311
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.0259
Gnomad4 FIN
AF:
0.0406
Gnomad4 NFE
AF:
0.0249
Gnomad4 OTH
AF:
0.0478
Alfa
AF:
0.0310
Hom.:
152
Bravo
AF:
0.0466
Asia WGS
AF:
0.0130
AC:
46
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021- -
Nephronophthisis 4 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabApr 11, 2023- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Senior-Loken syndrome 4 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Kidney disorder Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJul 01, 2018- -
Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
0.11
DANN
Benign
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12116997; hg19: chr1-5969245; COSMIC: COSV65394924; COSMIC: COSV65394924; API