rs12116997

Positions:

• chr1-5909185-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015102.5(NPHP4):​c.1470C>T​(p.Leu490=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,603,376 control chromosomes in the GnomAD database, including 989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (226 hom., cov: 33)
  • Exomes 𝑓: 0.027 (763 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.09

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-5909185-G-A is Benign according to our data. Variant chr1-5909185-G-A is described in ClinVar as [Benign]. Clinvar id is 260543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5909185-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.1470C>T	p.Leu490=	synonymous_variant	12/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.1470C>T	p.Leu490=	synonymous_variant	12/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6971 AN: 152048 Hom.: 226 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0292 AC: 6689 AN: 229090 Hom.: 159 AF XY: 0.0284 AC XY: 3528 AN XY: 124058

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.0308

Gnomad FIN exome AF: 0.0412

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0326

GnomAD4 exome AF: 0.0274 AC: 39767 AN: 1451210 Hom.: 763 Cov.: 32 AF XY: 0.0271 AC XY: 19544 AN XY: 720546

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0332

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0458 AC: 6971 AN: 152166 Hom.: 226 Cov.: 33 AF XY: 0.0455 AC XY: 3385 AN XY: 74400

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0249

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0310 Hom.: 152

Bravo AF: 0.0466

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Nephronophthisis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
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. -

Senior-Loken syndrome 4 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. -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2018

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.11
DANN	Benign	0.48

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: rs12116997; hg19: chr1-5969245; COSMIC: COSV65394924; COSMIC: COSV65394924;