rs62292468

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_153240.5(NPHP3):​c.2571-7T>C variant causes a splice region, 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, intron

Scores

2
Splicing: ADA: 0.00001937
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.191

Publications

3 publications found
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]

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.94).
BP6
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.
BS1
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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 102 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPHP3NM_153240.5 linkc.2571-7T>C splice_region_variant, intron_variant Intron 18 of 26 ENST00000337331.10 NP_694972.3 Q7Z494-1
NPHP3-ACAD11NR_037804.1 linkn.2577-7T>C splice_region_variant, intron_variant Intron 17 of 44

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NPHP3ENST00000337331.10 linkc.2571-7T>C splice_region_variant, intron_variant Intron 18 of 26 1 NM_153240.5 ENSP00000338766.5 Q7Z494-1

Frequencies

GnomAD3 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
GnomAD2 exomes
AF:
0.0304
AC:
7637
AN:
251272
AF XY:
0.0308
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 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
African (AFR)
AF:
0.00663
AC:
222
AN:
33460
American (AMR)
AF:
0.0108
AC:
484
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.0387
AC:
1012
AN:
26118
East Asian (EAS)
AF:
0.000126
AC:
5
AN:
39666
South Asian (SAS)
AF:
0.0110
AC:
948
AN:
86230
European-Finnish (FIN)
AF:
0.0308
AC:
1645
AN:
53414
Middle Eastern (MID)
AF:
0.0203
AC:
117
AN:
5764
European-Non Finnish (NFE)
AF:
0.0475
AC:
52832
AN:
1111274
Other (OTH)
AF:
0.0344
AC:
2075
AN:
60370
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
2525
5050
7574
10099
12624
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
1908
3816
5724
7632
9540
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0288
AC:
4392
AN:
152290
Hom.:
102
Cov.:
32
AF XY:
0.0272
AC XY:
2022
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.00784
AC:
326
AN:
41578
American (AMR)
AF:
0.0166
AC:
254
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.0398
AC:
138
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00952
AC:
46
AN:
4830
European-Finnish (FIN)
AF:
0.0297
AC:
315
AN:
10612
Middle Eastern (MID)
AF:
0.0136
AC:
4
AN:
294
European-Non Finnish (NFE)
AF:
0.0475
AC:
3232
AN:
68002
Other (OTH)
AF:
0.0151
AC:
32
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
217
435
652
870
1087
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
52
104
156
208
260
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Feb 19, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 11, 2013
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Renal-hepatic-pancreatic dysplasia 1 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Focal segmental glomerulosclerosis Benign:1
Apr 01, 2019
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nephronophthisis 3 Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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
PhyloP100
-0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs62292468; hg19: chr3-132409501; API