rs143323188

Positions:

• chr1-5978416-AG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000378156.9(NPHP4):​c.136-4del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000908 in 1,599,758 control chromosomes in the GnomAD database, including 25 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (3 hom., cov: 29)
  • Exomes 𝑓: 0.00090 (22 hom.)
• Consequence: NPHP4 ENST00000378156.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.672

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 -16 ACMG points.

• BP6: Variant 1-5978416-AG-A is Benign according to our data. Variant chr1-5978416-AG-A is described in ClinVar as [Likely_benign]. Clinvar id is 220231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-5978416-AG-A is described in Lovd as [Benign]. Variant chr1-5978416-AG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00101 (154/152260) while in subpopulation EAS AF= 0.0283 (147/5186). AF 95% confidence interval is 0.0246. There are 3 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.136-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.136-4del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152142 Hom.: 3 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00215 AC: 486 AN: 226326 Hom.: 12 AF XY: 0.00202 AC XY: 248 AN XY: 122746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000312

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0280

Gnomad SAS exome AF: 0.000432

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000395

Gnomad OTH exome AF: 0.00142

GnomAD4 exome AF: 0.000897 AC: 1298 AN: 1447498 Hom.: 22 Cov.: 31 AF XY: 0.000849 AC XY: 610 AN XY: 718688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000468

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.000333

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000308

Gnomad4 OTH exome AF: 0.000834

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152260 Hom.: 3 Cov.: 29 AF XY: 0.00121 AC XY: 90 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0283

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 03, 2021

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Renal dysplasia and retinal aplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143323188; hg19: chr1-6038476;