1-5880198-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015102.5(NPHP4):​c.2527C>G​(p.Pro843Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,524 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P843S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

11
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.96
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.4078042).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHP4NM_015102.5 linkc.2527C>G p.Pro843Ala missense_variant Exon 19 of 30 ENST00000378156.9 NP_055917.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHP4ENST00000378156.9 linkc.2527C>G p.Pro843Ala missense_variant Exon 19 of 30 1 NM_015102.5 ENSP00000367398.4 O75161-1
NPHP4ENST00000378169.7 linkn.*1428C>G non_coding_transcript_exon_variant Exon 16 of 27 1 ENSP00000367411.3 D6RA06
NPHP4ENST00000489180.6 linkn.2524C>G non_coding_transcript_exon_variant Exon 19 of 33 2 ENSP00000423747.1 O75161-2
NPHP4ENST00000378169.7 linkn.*1428C>G 3_prime_UTR_variant Exon 16 of 27 1 ENSP00000367411.3 D6RA06

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461304
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
726880
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.00000826
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 Uncertain:1
Dec 23, 2023
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nephronophthisis Uncertain:1
Aug 24, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.046
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.82
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.41
T;T
MetaSVM
Uncertain
0.58
D
MutationAssessor
Uncertain
2.7
M;.
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-2.6
D;.
REVEL
Uncertain
0.32
Sift
Uncertain
0.021
D;.
Sift4G
Benign
0.13
T;D
Polyphen
1.0
D;.
Vest4
0.28
MutPred
0.21
Loss of glycosylation at P843 (P = 0.0236);.;
MVP
0.95
MPC
0.33
ClinPred
0.87
D
GERP RS
5.2
Varity_R
0.078
gMVP
0.31

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: rs775263560; hg19: chr1-5940258; COSMIC: COSV65397292; COSMIC: COSV65397292; API