1-5877267-C-T

Position:

• chr1-5877267-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.2643G>A​(p.Ala881Ala) 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 1,600,490 control chromosomes in the GnomAD database, including 19,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1382 hom., cov: 35)
  • Exomes 𝑓: 0.16 (18498 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.70

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]

NPHP4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-5877267-C-T is Benign according to our data. Variant chr1-5877267-C-T is described in ClinVar as [Benign]. Clinvar id is 95677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5877267-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.7 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	Protein	UniProt
NPHP4	NM_015102.5	c.2643G>A	p.Ala881Ala	synonymous_variant	20/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2643G>A	p.Ala881Ala	synonymous_variant	20/30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*1544G>A		non_coding_transcript_exon_variant	17/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*191G>A		non_coding_transcript_exon_variant	21/33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*1544G>A		3_prime_UTR_variant	17/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.*191G>A		3_prime_UTR_variant	21/33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18101 AN: 152180 Hom.: 1383 Cov.: 35

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.0751

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.140

GnomAD3 exomes AF: 0.131 AC: 31812 AN: 242056 Hom.: 2324 AF XY: 0.136 AC XY: 17854 AN XY: 131530

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.0747

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.0740

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.156 AC: 225883 AN: 1448192 Hom.: 18498 Cov.: 37 AF XY: 0.155 AC XY: 111683 AN XY: 718344

Gnomad4 AFR exome AF: 0.0258

Gnomad4 AMR exome AF: 0.0811

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.0763

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.119 AC: 18095 AN: 152298 Hom.: 1382 Cov.: 35 AF XY: 0.118 AC XY: 8794 AN XY: 74464

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.229

Gnomad4 EAS AF: 0.0749

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.138

Alfa AF: 0.161 Hom.: 2776

Bravo AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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 04, 2021	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.47
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3747990; hg19: chr1-5937327; COSMIC: COSV65396938; COSMIC: COSV65396938;