rs7520105

Positions:

• chr1-5927636-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):​c.1441+13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,595,044 control chromosomes in the GnomAD database, including 21,666 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2301 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19365 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.540

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-5927636-T-C is Benign according to our data. Variant chr1-5927636-T-C is described in ClinVar as [Benign]. Clinvar id is 95671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5927636-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.1441+13A>G		intron_variant		ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.1441+13A>G		intron_variant		1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25985 AN: 152042 Hom.: 2301 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.0751

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.145 AC: 35805 AN: 246092 Hom.: 2852 AF XY: 0.146 AC XY: 19475 AN XY: 133538

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.0875

Gnomad ASJ exome AF: 0.221

Gnomad EAS exome AF: 0.0770

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.161 AC: 232402 AN: 1442884 Hom.: 19365 Cov.: 32 AF XY: 0.160 AC XY: 114058 AN XY: 714284

Gnomad4 AFR exome AF: 0.215

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.171 AC: 26000 AN: 152160 Hom.: 2301 Cov.: 32 AF XY: 0.169 AC XY: 12547 AN XY: 74420

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.0749

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.182

Alfa AF: 0.177 Hom.: 474

Bravo AF: 0.174

Asia WGS AF: 0.109 AC: 378 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Nephronophthisis 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Senior-Loken syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7520105; hg19: chr1-5987696; COSMIC: COSV65395165;