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GeneBe

rs34373111

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_015102.5(NPHP4):​c.2031C>T​(p.Pro677=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,613,998 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 26 hom., cov: 33)
Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

NPHP4
NM_015102.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.50
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 Benign. Variant got -21 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=-0.73).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-5904729-G-A is Benign according to our data. Variant chr1-5904729-G-A is described in ClinVar as [Benign]. Clinvar id is 240966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5904729-G-A is described in Lovd as [Likely_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=-2.5 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 = 0.0101 (1541/152304) while in subpopulation AFR AF= 0.0348 (1446/41558). AF 95% confidence interval is 0.0333. There are 26 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 33. 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 26 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NPHP4NM_015102.5 linkuse as main transcriptc.2031C>T p.Pro677= synonymous_variant 16/30 ENST00000378156.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NPHP4ENST00000378156.9 linkuse as main transcriptc.2031C>T p.Pro677= synonymous_variant 16/301 NM_015102.5 P2O75161-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0101
AC:
1535
AN:
152186
Hom.:
25
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0348
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00366
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.0119
GnomAD3 exomes
AF:
0.00240
AC:
599
AN:
249304
Hom.:
14
AF XY:
0.00165
AC XY:
223
AN XY:
135250
show subpopulations
Gnomad AFR exome
AF:
0.0331
Gnomad AMR exome
AF:
0.00153
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.000139
Gnomad NFE exome
AF:
0.000115
Gnomad OTH exome
AF:
0.00231
GnomAD4 exome
AF:
0.00107
AC:
1566
AN:
1461694
Hom.:
29
Cov.:
31
AF XY:
0.000931
AC XY:
677
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.0342
Gnomad4 AMR exome
AF:
0.00219
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000185
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.0000773
Gnomad4 OTH exome
AF:
0.00315
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0101
AC:
1541
AN:
152304
Hom.:
26
Cov.:
33
AF XY:
0.00949
AC XY:
707
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0348
Gnomad4 AMR
AF:
0.00366
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.0118
Alfa
AF:
0.00553
Hom.:
7
Bravo
AF:
0.0118
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Senior-Loken syndrome 4 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. -
Nephronophthisis Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Nephronophthisis 4 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
-0.73
CADD
Benign
0.57
DANN
Benign
0.69

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: rs34373111; hg19: chr1-5964789; API