rs41280814

chr1-5887248-G-A

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.2485+38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,572,348 control chromosomes in the GnomAD database, including 19,477 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18115 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.10

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=-0.85).
• BP6: Variant 1-5887248-G-A is Benign according to our data. Variant chr1-5887248-G-A is described in ClinVar as [Benign]. Clinvar id is 260546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.2485+38C>T		intron_variant		ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.2485+38C>T		intron_variant		1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17988 AN: 152154 Hom.: 1363 Cov.: 33

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.136

GnomAD3 exomes AF: 0.134 AC: 26627 AN: 198424 Hom.: 1991 AF XY: 0.138 AC XY: 14828 AN XY: 107794

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.0789

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.0795

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.156 AC: 221859 AN: 1420076 Hom.: 18115 Cov.: 30 AF XY: 0.156 AC XY: 109355 AN XY: 702458

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.0788

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.118 AC: 17983 AN: 152272 Hom.: 1362 Cov.: 33 AF XY: 0.117 AC XY: 8728 AN XY: 74454

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.0754

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.165

Gnomad4 OTH AF: 0.135

Alfa AF: 0.152 Hom.: 389

Bravo AF: 0.113

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Nephronophthisis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.036
Dann	Benign	0.64

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: rs41280814; hg19: chr1-5947308; COSMIC: COSV65397198; COSMIC: COSV65397198;