1-5904788-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015102.5(NPHP4):​c.1972C>G​(p.Arg658Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R658Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

NPHP4
NM_015102.5 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0520
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0720295).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHP4NM_015102.5 linkc.1972C>G p.Arg658Gly missense_variant Exon 16 of 30 ENST00000378156.9 NP_055917.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHP4ENST00000378156.9 linkc.1972C>G p.Arg658Gly missense_variant Exon 16 of 30 1 NM_015102.5 ENSP00000367398.4 O75161-1
NPHP4ENST00000378169.7 linkn.*873C>G non_coding_transcript_exon_variant Exon 13 of 27 1 ENSP00000367411.3 D6RA06
NPHP4ENST00000489180.6 linkn.1969C>G non_coding_transcript_exon_variant Exon 16 of 33 2 ENSP00000423747.1 O75161-2
NPHP4ENST00000378169.7 linkn.*873C>G 3_prime_UTR_variant Exon 13 of 27 1 ENSP00000367411.3 D6RA06

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461682
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727122
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.026
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
14
DANN
Benign
0.91
DEOGEN2
Benign
0.089
T;.
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.022
N
LIST_S2
Benign
0.63
T;T
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.072
T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
1.4
L;.
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-0.18
N;.
REVEL
Uncertain
0.29
Sift
Benign
0.46
T;.
Sift4G
Benign
0.35
T;T
Polyphen
0.0030
B;.
Vest4
0.13
MutPred
0.33
Loss of solvent accessibility (P = 0.0044);.;
MVP
0.78
MPC
0.081
ClinPred
0.073
T
GERP RS
2.0
Varity_R
0.072
gMVP
0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-5964848; API