rs6794496

Variant names:

• chr3-132682756-C-T
• rs6794496
• NM_153240.5:c.3759G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_153240.5(NPHP3):​c.3759G>A​(p.Leu1253Leu) 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
• Publications: 18 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.3759G>A	p.Leu1253Leu	synonymous_variant	Exon 26 of 27	ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.3765G>A		non_coding_transcript_exon_variant	Exon 25 of 45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.3759G>A	p.Leu1253Leu	synonymous_variant	Exon 26 of 27	1	NM_153240.5	ENSP00000338766.5
NPHP3-ACAD11	ENST00000632629.1	c.405G>A	p.Leu135Leu	synonymous_variant	Exon 3 of 5	2		ENSP00000488520.1

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

GnomAD2 exomes AF: 0.161 AC: 40455 AN: 251240 AF XY: 0.161

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 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

African (AFR) AF: 0.109 AC: 3630 AN: 33454

American (AMR) AF: 0.0801 AC: 3581 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 2248 AN: 26120

East Asian (EAS) AF: 0.590 AC: 23388 AN: 39656

South Asian (SAS) AF: 0.168 AC: 14459 AN: 86206

European-Finnish (FIN) AF: 0.167 AC: 8930 AN: 53404

Middle Eastern (MID) AF: 0.104 AC: 600 AN: 5764

European-Non Finnish (NFE) AF: 0.129 AC: 143459 AN: 1110486

Other (OTH) AF: 0.150 AC: 9024 AN: 60344

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

African (AFR) AF: 0.112 AC: 4665 AN: 41534

American (AMR) AF: 0.107 AC: 1628 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 294 AN: 3468

East Asian (EAS) AF: 0.579 AC: 2996 AN: 5172

South Asian (SAS) AF: 0.193 AC: 933 AN: 4822

European-Finnish (FIN) AF: 0.168 AC: 1777 AN: 10570

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9035 AN: 67970

Other (OTH) AF: 0.140 AC: 296 AN: 2108

Alfa AF: 0.136 Hom.: 8199

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

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 22, 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

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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: 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. -

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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.28
CADD	Benign	9.3
DANN	Benign	0.75
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6794496; hg19: chr3-132401600; COSMIC: COSV107300382; COSMIC: COSV107300382;