rs115526767

Positions:

• chr1-5864458-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015102.5(NPHP4):​c.3876C>T​(p.Gly1292=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,605,318 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 33)
  • Exomes 𝑓: 0.016 (219 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.52

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=-0.83).
• BP6: Variant 1-5864458-G-A is Benign according to our data. Variant chr1-5864458-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5864458-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0096 (1463/152322) while in subpopulation NFE AF= 0.0161 (1095/68020). AF 95% confidence interval is 0.0153. There are 14 homozygotes in gnomad4. There are 675 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.3876C>T	p.Gly1292=	synonymous_variant	28/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.3876C>T	p.Gly1292=	synonymous_variant	28/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152204 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00765

GnomAD3 exomes AF: 0.00930 AC: 2132 AN: 229252 Hom.: 10 AF XY: 0.00941 AC XY: 1177 AN XY: 125120

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.00447

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00360

Gnomad FIN exome AF: 0.00572

Gnomad NFE exome AF: 0.0161

Gnomad OTH exome AF: 0.00953

GnomAD4 exome AF: 0.0156 AC: 22728 AN: 1452996 Hom.: 219 Cov.: 32 AF XY: 0.0152 AC XY: 10940 AN XY: 721954

Gnomad4 AFR exome AF: 0.00258

Gnomad4 AMR exome AF: 0.00455

Gnomad4 ASJ exome AF: 0.00220

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00395

Gnomad4 FIN exome AF: 0.00700

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.00960 AC: 1463 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00906 AC XY: 675 AN XY: 74484

Gnomad4 AFR AF: 0.00298

Gnomad4 AMR AF: 0.00816

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.0142 Hom.: 12

Bravo AF: 0.00969

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2013	- -

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. -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Nephronophthisis 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.51
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs115526767; hg19: chr1-5924518; COSMIC: COSV105928980; COSMIC: COSV105928980;