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rs114545322

Positions:

Variant summary

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

The NM_015102.5(NPHP4):​c.2724G>A​(p.Ser908=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,603,148 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 195 hom., cov: 35)
Exomes 𝑓: 0.0031 ( 174 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.892
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-5877186-C-T is Benign according to our data. Variant chr1-5877186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.892 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP4NM_015102.5 linkuse as main transcriptc.2724G>A p.Ser908= synonymous_variant 20/30 ENST00000378156.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP4ENST00000378156.9 linkuse as main transcriptc.2724G>A p.Ser908= synonymous_variant 20/301 NM_015102.5 P2O75161-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0278
AC:
4233
AN:
152246
Hom.:
194
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00922
Gnomad ASJ
AF:
0.000865
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000558
Gnomad OTH
AF:
0.0196
GnomAD3 exomes
AF:
0.00671
AC:
1544
AN:
230026
Hom.:
60
AF XY:
0.00528
AC XY:
662
AN XY:
125384
show subpopulations
Gnomad AFR exome
AF:
0.0972
Gnomad AMR exome
AF:
0.00501
Gnomad ASJ exome
AF:
0.000937
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000359
Gnomad OTH exome
AF:
0.00493
GnomAD4 exome
AF:
0.00305
AC:
4431
AN:
1450782
Hom.:
174
Cov.:
35
AF XY:
0.00263
AC XY:
1894
AN XY:
720486
show subpopulations
Gnomad4 AFR exome
AF:
0.0999
Gnomad4 AMR exome
AF:
0.00584
Gnomad4 ASJ exome
AF:
0.00104
Gnomad4 EAS exome
AF:
0.0000255
Gnomad4 SAS exome
AF:
0.000178
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000388
Gnomad4 OTH exome
AF:
0.00596
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0279
AC:
4246
AN:
152366
Hom.:
195
Cov.:
35
AF XY:
0.0272
AC XY:
2027
AN XY:
74514
show subpopulations
Gnomad4 AFR
AF:
0.0968
Gnomad4 AMR
AF:
0.00921
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000558
Gnomad4 OTH
AF:
0.0194
Alfa
AF:
0.0135
Hom.:
38
Bravo
AF:
0.0325
Asia WGS
AF:
0.00462
AC:
16
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 04, 2013- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Kidney disorder Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJun 01, 2018- -
Senior-Loken syndrome 4 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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;C1847013:Nephronophthisis 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 09, 2021- -
Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMay 04, 2021- -
Nephronophthisis 4 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
1.0
DANN
Benign
0.60
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs114545322; hg19: chr1-5937246; API