rs146250226

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_153240.5(NPHP3):ā€‹c.1082C>Gā€‹(p.Ser361Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000619 in 1,501,520 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 33)
Exomes š‘“: 0.000056 ( 0 hom. )

Consequence

NPHP3
NM_153240.5 missense

Scores

4
10
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.86
Variant links:
Genes affected
NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]
NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.088161975).
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152042) while in subpopulation EAS AF= 0.00347 (18/5182). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPHP3NM_153240.5 linkuse as main transcriptc.1082C>G p.Ser361Cys missense_variant 6/27 ENST00000337331.10 NP_694972.3 Q7Z494-1
NPHP3-ACAD11NR_037804.1 linkuse as main transcriptn.1186C>G non_coding_transcript_exon_variant 6/45

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPHP3ENST00000337331.10 linkuse as main transcriptc.1082C>G p.Ser361Cys missense_variant 6/271 NM_153240.5 ENSP00000338766.5 Q7Z494-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
151924
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00347
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
GnomAD3 exomes
AF:
0.000240
AC:
55
AN:
229036
Hom.:
0
AF XY:
0.000185
AC XY:
23
AN XY:
124142
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00307
Gnomad SAS exome
AF:
0.0000790
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000556
AC:
75
AN:
1349478
Hom.:
0
Cov.:
23
AF XY:
0.0000459
AC XY:
31
AN XY:
675304
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00177
Gnomad4 SAS exome
AF:
0.0000381
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000712
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152042
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00347
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000204
ExAC
AF:
0.000231
AC:
28
Asia WGS
AF:
0.000291
AC:
1
AN:
3452

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 18, 2017The S361C variant in the NPHP3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S361C variant is observed in 27/7898 (0.3%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The S361C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret S361C as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 20, 2017- -
Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Nephronophthisis Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 10, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
T
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.088
T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Uncertain
2.1
M
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
-1.1
N
REVEL
Uncertain
0.62
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0020
D
Polyphen
1.0
D
Vest4
0.89
MVP
0.97
MPC
0.71
ClinPred
0.13
T
GERP RS
6.0
Varity_R
0.28
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs146250226; hg19: chr3-132432006; API