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rs78527322

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_153240.5(NPHP3):​c.450G>A​(p.Ala150=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,602,544 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 16 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 32 hom. )

Consequence

NPHP3
NM_153240.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.224
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=-0.38).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-132719774-C-T is Benign according to our data. Variant chr3-132719774-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132719774-C-T is described in Lovd as [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=0.224 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0086 (1306/151946) while in subpopulation AFR AF= 0.027 (1120/41460). AF 95% confidence interval is 0.0257. There are 16 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP3NM_153240.5 linkuse as main transcriptc.450G>A p.Ala150= synonymous_variant 2/27 ENST00000337331.10
NPHP3-ACAD11NR_037804.1 linkuse as main transcriptn.554G>A non_coding_transcript_exon_variant 2/45

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP3ENST00000337331.10 linkuse as main transcriptc.450G>A p.Ala150= synonymous_variant 2/271 NM_153240.5 P1Q7Z494-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00860
AC:
1305
AN:
151830
Hom.:
16
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0271
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00524
Gnomad ASJ
AF:
0.00346
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.0000956
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.00106
Gnomad OTH
AF:
0.00623
GnomAD3 exomes
AF:
0.00338
AC:
846
AN:
250054
Hom.:
16
AF XY:
0.00285
AC XY:
386
AN XY:
135240
show subpopulations
Gnomad AFR exome
AF:
0.0289
Gnomad AMR exome
AF:
0.00366
Gnomad ASJ exome
AF:
0.00338
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00168
Gnomad FIN exome
AF:
0.000417
Gnomad NFE exome
AF:
0.00123
Gnomad OTH exome
AF:
0.00328
GnomAD4 exome
AF:
0.00182
AC:
2647
AN:
1450598
Hom.:
32
Cov.:
28
AF XY:
0.00177
AC XY:
1281
AN XY:
721704
show subpopulations
Gnomad4 AFR exome
AF:
0.0304
Gnomad4 AMR exome
AF:
0.00388
Gnomad4 ASJ exome
AF:
0.00314
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00180
Gnomad4 FIN exome
AF:
0.000530
Gnomad4 NFE exome
AF:
0.000868
Gnomad4 OTH exome
AF:
0.00299
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00860
AC:
1306
AN:
151946
Hom.:
16
Cov.:
32
AF XY:
0.00831
AC XY:
617
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.0270
Gnomad4 AMR
AF:
0.00523
Gnomad4 ASJ
AF:
0.00346
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.0000956
Gnomad4 NFE
AF:
0.00106
Gnomad4 OTH
AF:
0.00617
Alfa
AF:
0.00422
Hom.:
5
Bravo
AF:
0.0102
Asia WGS
AF:
0.00434
AC:
15
AN:
3470

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 29, 2014- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxAug 02, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Renal-hepatic-pancreatic dysplasia 1 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. -
Kidney disorder Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenFeb 01, 2018- -
NPHP3-related Meckel-like syndrome Benign:1
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
not provided Benign:1
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Nephronophthisis 3 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
-0.38
CADD
Benign
13
DANN
Benign
0.81

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: rs78527322; hg19: chr3-132438618; API