rs41280800

Positions:

• chr1-5873324-C-G

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.3243G>C​(p.Gly1081=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0232 in 1,613,720 control chromosomes in the GnomAD database, including 548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (34 hom., cov: 33)
  • Exomes 𝑓: 0.024 (514 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00100

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=-0.81).
• BP6: Variant 1-5873324-C-G is Benign according to our data. Variant chr1-5873324-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 95681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5873324-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.001 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0162 (2474/152292) while in subpopulation NFE AF= 0.0255 (1731/68006). AF 95% confidence interval is 0.0245. There are 34 homozygotes in gnomad4. There are 1116 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.3243G>C	p.Gly1081=	synonymous_variant	23/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.3243G>C	p.Gly1081=	synonymous_variant	23/30	1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2474 AN: 152174 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0145 AC: 3621 AN: 249198 Hom.: 38 AF XY: 0.0146 AC XY: 1979 AN XY: 135182

Gnomad AFR exome AF: 0.00684

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00571

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0239 AC: 34953 AN: 1461428 Hom.: 514 Cov.: 31 AF XY: 0.0231 AC XY: 16797 AN XY: 726996

Gnomad4 AFR exome AF: 0.00585

Gnomad4 AMR exome AF: 0.0118

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00545

Gnomad4 NFE exome AF: 0.0286

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0162 AC: 2474 AN: 152292 Hom.: 34 Cov.: 33 AF XY: 0.0150 AC XY: 1116 AN XY: 74450

Gnomad4 AFR AF: 0.00734

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00462

Gnomad4 NFE AF: 0.0255

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0235 Hom.: 41

Bravo AF: 0.0175

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0255

EpiControl AF: 0.0269

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2012	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 16, 2017

- -

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 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nephronophthisis 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.88
DANN	Benign	0.47
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: rs41280800; hg19: chr1-5933384; COSMIC: COSV65393889; COSMIC: COSV65393889;