rs143323188

Variant names:

• chr1-5978416-AG-A
• rs143323188
• NM_015102.5:c.136-4delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.136-4delC variant causes a splice region, 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 NM_015102.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.672
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 220231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.136-4delC		splice_region intron	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.-1087-9158delC		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.-1094-4delC		splice_region intron	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.136-4delC		splice_region intron	N/A	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.136-4delC		splice_region intron	N/A	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.136-4delC		splice_region intron	N/A	ENSP00000423747.1	O75161-2

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

GnomAD2 exomes AF: 0.00215 AC: 486 AN: 226326 AF XY: 0.00202

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.0000468 AC: 2 AN: 42702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.0303 AC: 1184 AN: 39096

South Asian (SAS) AF: 0.000333 AC: 28 AN: 83964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000308 AC: 34 AN: 1105296

Other (OTH) AF: 0.000834 AC: 50 AN: 59932

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

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0283 AC: 147 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis (2)
-	-	1	Kidney disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Renal dysplasia and retinal aplasia (1)
-	-	1	Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs143323188; hg19: chr1-6038476;