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GeneBe

rs62292468

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153240.5(NPHP3):​c.2571-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,306 control chromosomes in the GnomAD database, including 1,507 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 102 hom., cov: 32)
Exomes 𝑓: 0.041 ( 1405 hom. )

Consequence

NPHP3
NM_153240.5 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00001937
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.191
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 -20 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=-0.94).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-132690657-A-G is Benign according to our data. Variant chr3-132690657-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 96512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132690657-A-G is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0288 (4392/152290) while in subpopulation NFE AF= 0.0475 (3232/68002). AF 95% confidence interval is 0.0462. There are 102 homozygotes in gnomad4. There are 2022 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 102 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP3NM_153240.5 linkuse as main transcriptc.2571-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000337331.10
NPHP3-ACAD11NR_037804.1 linkuse as main transcriptn.2577-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP3ENST00000337331.10 linkuse as main transcriptc.2571-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_153240.5 P1Q7Z494-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0289
AC:
4397
AN:
152172
Hom.:
103
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00784
Gnomad AMI
AF:
0.0493
Gnomad AMR
AF:
0.0167
Gnomad ASJ
AF:
0.0398
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00952
Gnomad FIN
AF:
0.0297
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0475
Gnomad OTH
AF:
0.0162
GnomAD3 exomes
AF:
0.0304
AC:
7637
AN:
251272
Hom.:
187
AF XY:
0.0308
AC XY:
4189
AN XY:
135818
show subpopulations
Gnomad AFR exome
AF:
0.00715
Gnomad AMR exome
AF:
0.0107
Gnomad ASJ exome
AF:
0.0386
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0101
Gnomad FIN exome
AF:
0.0302
Gnomad NFE exome
AF:
0.0494
Gnomad OTH exome
AF:
0.0307
GnomAD4 exome
AF:
0.0406
AC:
59340
AN:
1461016
Hom.:
1405
Cov.:
31
AF XY:
0.0397
AC XY:
28871
AN XY:
726884
show subpopulations
Gnomad4 AFR exome
AF:
0.00663
Gnomad4 AMR exome
AF:
0.0108
Gnomad4 ASJ exome
AF:
0.0387
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0110
Gnomad4 FIN exome
AF:
0.0308
Gnomad4 NFE exome
AF:
0.0475
Gnomad4 OTH exome
AF:
0.0344
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0288
AC:
4392
AN:
152290
Hom.:
102
Cov.:
32
AF XY:
0.0272
AC XY:
2022
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00784
Gnomad4 AMR
AF:
0.0166
Gnomad4 ASJ
AF:
0.0398
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00952
Gnomad4 FIN
AF:
0.0297
Gnomad4 NFE
AF:
0.0475
Gnomad4 OTH
AF:
0.0151
Alfa
AF:
0.0410
Hom.:
69
Bravo
AF:
0.0280
Asia WGS
AF:
0.00520
AC:
18
AN:
3476
EpiCase
AF:
0.0481
EpiControl
AF:
0.0487

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 19, 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. -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 11, 2013- -
Renal-hepatic-pancreatic dysplasia 1 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. -
NPHP3-related Meckel-like syndrome Benign:1
Likely 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 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- -
Focal segmental glomerulosclerosis Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenApr 01, 2019- -
Nephronophthisis 3 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
-0.94
CADD
Benign
0.51
DANN
Benign
0.35
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000019
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.010
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: rs62292468; hg19: chr3-132409501; API