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GeneBe

rs41280800

chr1-5873324-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015102.5(NPHP4):c.3243G>C(p.Gly1081=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,720 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 34 hom., cov: 33)
Exomes 𝑓: 0.024 ( 514 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.00100
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=-0.81).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-5873324-C-G is Benign according to our data. Variant chr1-5873324-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 95681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5873324-C-G is described in Lovd as [Likely_benign].
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=-0.001 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2474/152292) while in subpopulation NFE AF= 0.0255 (1731/68006). AF 95% confidence interval is 0.0245. There are 34 homozygotes in gnomad4. There are 1116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP4NM_015102.5 linkuse as main transcriptc.3243G>C p.Gly1081= synonymous_variant 23/30 ENST00000378156.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP4ENST00000378156.9 linkuse as main transcriptc.3243G>C p.Gly1081= synonymous_variant 23/301 NM_015102.5 P2O75161-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0163
AC:
2474
AN:
152174
Hom.:
34
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00736
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0186
Gnomad ASJ
AF:
0.0170
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000621
Gnomad FIN
AF:
0.00462
Gnomad MID
AF:
0.0158
Gnomad NFE
AF:
0.0255
Gnomad OTH
AF:
0.0177
GnomAD3 exomes
AF:
0.0145
AC:
3621
AN:
249198
Hom.:
38
AF XY:
0.0146
AC XY:
1979
AN XY:
135182
show subpopulations
Gnomad AFR exome
AF:
0.00684
Gnomad AMR exome
AF:
0.0110
Gnomad ASJ exome
AF:
0.0192
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.00141
Gnomad FIN exome
AF:
0.00571
Gnomad NFE exome
AF:
0.0236
Gnomad OTH exome
AF:
0.0185
GnomAD4 exome
AF:
0.0239
AC:
34953
AN:
1461428
Hom.:
514
Cov.:
31
AF XY:
0.0231
AC XY:
16797
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.00585
Gnomad4 AMR exome
AF:
0.0118
Gnomad4 ASJ exome
AF:
0.0194
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00119
Gnomad4 FIN exome
AF:
0.00545
Gnomad4 NFE exome
AF:
0.0286
Gnomad4 OTH exome
AF:
0.0237
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0162
AC:
2474
AN:
152292
Hom.:
34
Cov.:
33
AF XY:
0.0150
AC XY:
1116
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00734
Gnomad4 AMR
AF:
0.0186
Gnomad4 ASJ
AF:
0.0170
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00462
Gnomad4 NFE
AF:
0.0255
Gnomad4 OTH
AF:
0.0175
Alfa
AF:
0.0235
Hom.:
41
Bravo
AF:
0.0175
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0255
EpiControl
AF:
0.0269

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 28, 2012- -
Kidney disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 16, 2017- -
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. -
Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
Nephronophthisis 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
Cadd
Benign
0.88
Dann
Benign
0.47
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: rs41280800; hg19: chr1-5933384; COSMIC: COSV65393889; COSMIC: COSV65393889; API