rs6794496

Positions:

• chr3-132682756-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_153240.5(NPHP3):​c.3759G>A​(p.Leu1253=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,612,284 control chromosomes in the GnomAD database, including 21,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2125 hom., cov: 32)
  • Exomes 𝑓: 0.14 (19700 hom.)
• Consequence: NPHP3 NM_153240.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.58

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:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-132682756-C-T is Benign according to our data. Variant chr3-132682756-C-T is described in ClinVar as [Benign]. Clinvar id is 262710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132682756-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.3759G>A	p.Leu1253=	synonymous_variant	26/27	ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.3765G>A		non_coding_transcript_exon_variant	25/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.3759G>A	p.Leu1253=	synonymous_variant	26/27	1	NM_153240.5	ENSP00000338766	P1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21765 AN: 152008 Hom.: 2134 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0848

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.161 AC: 40455 AN: 251240 Hom.: 5226 AF XY: 0.161 AC XY: 21827 AN XY: 135788

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.0855

Gnomad EAS exome AF: 0.585

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.143 AC: 209319 AN: 1460158 Hom.: 19700 Cov.: 30 AF XY: 0.144 AC XY: 104832 AN XY: 726416

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0801

Gnomad4 ASJ exome AF: 0.0861

Gnomad4 EAS exome AF: 0.590

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.143 AC: 21761 AN: 152126 Hom.: 2125 Cov.: 32 AF XY: 0.148 AC XY: 10997 AN XY: 74370

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.0848

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.140

Alfa AF: 0.131 Hom.: 3543

Bravo AF: 0.137

Asia WGS AF: 0.317 AC: 1100 AN: 3476

EpiCase AF: 0.123

EpiControl AF: 0.119

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Renal-hepatic-pancreatic dysplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nephronophthisis 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.28
CADD	Benign	9.3
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs6794496; hg19: chr3-132401600;