rs1287634

chr1-5865311-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.3645-38C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 1,482,882 control chromosomes in the GnomAD database, including 122,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10196 hom., cov: 33)
  • Exomes 𝑓: 0.41 (112352 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.09

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=-0.9).
• BP6: Variant 1-5865311-G-A is Benign according to our data. Variant chr1-5865311-G-A is described in ClinVar as [Benign]. Clinvar id is 260559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.3645-38C>T		intron_variant		ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.3645-38C>T		intron_variant		1	NM_015102.5	P2

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53654 AN: 152066 Hom.: 10194 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.362

GnomAD3 exomes AF: 0.389 AC: 48526 AN: 124902 Hom.: 9771 AF XY: 0.393 AC XY: 25404 AN XY: 64614

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.368

Gnomad ASJ exome AF: 0.474

Gnomad EAS exome AF: 0.252

Gnomad SAS exome AF: 0.435

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.408 AC: 542555 AN: 1330696 Hom.: 112352 Cov.: 29 AF XY: 0.409 AC XY: 264386 AN XY: 647122

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.366

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.417

Gnomad4 OTH exome AF: 0.402

GnomAD4 genome AF: 0.353 AC: 53673 AN: 152186 Hom.: 10196 Cov.: 33 AF XY: 0.355 AC XY: 26412 AN XY: 74398

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.369

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.418

Gnomad4 OTH AF: 0.359

Alfa AF: 0.408 Hom.: 21367

Bravo AF: 0.339

Asia WGS AF: 0.376 AC: 1305 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	-0.90
Cadd	Benign	0.84
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1287634; hg19: chr1-5925371; COSMIC: COSV65395132; COSMIC: COSV65395132;