1-5905321-C-T

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.1926G>A(p.Glu642=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,612,892 control chromosomes in the GnomAD database, including 19,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1356 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18497 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.740

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=-0.7).
• BP6: Variant 1-5905321-C-T is Benign according to our data. Variant chr1-5905321-C-T is described in ClinVar as [Benign]. Clinvar id is 95673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5905321-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.1926G>A	p.Glu642=	synonymous_variant	15/30	ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.1926G>A	p.Glu642=	synonymous_variant	15/30	1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17947 AN: 152132 Hom.: 1357 Cov.: 33

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0743

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.132 AC: 32824 AN: 249286 Hom.: 2505 AF XY: 0.135 AC XY: 18271 AN XY: 135238

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.0768

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.155 AC: 226534 AN: 1460642 Hom.: 18497 Cov.: 32 AF XY: 0.155 AC XY: 112298 AN XY: 726642

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.0816

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.0765

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.118 AC: 17940 AN: 152250 Hom.: 1356 Cov.: 33 AF XY: 0.117 AC XY: 8715 AN XY: 74440

Gnomad4 AFR AF: 0.0327

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.0741

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.135

Alfa AF: 0.159 Hom.: 2795

Bravo AF: 0.113

Asia WGS AF: 0.100 AC: 346 AN: 3478

EpiCase AF: 0.180

EpiControl AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:7

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	-	- -

Nephronophthisis 4 Benign:2

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. -
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 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

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	1.5
Dann	Benign	0.53

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: rs12120967; hg19: chr1-5965381; COSMIC: COSV65395162;