rs201335783

Variant names:

• chr1-5866476-AG-A
• rs201335783
• NM_015102.5:c.3559-19delC

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.3559-19delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,489,700 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0860
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 1-5866476-AG-A is Benign according to our data. Variant chr1-5866476-AG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00287 (438/152354) while in subpopulation AMR AF = 0.00562 (86/15310). AF 95% confidence interval is 0.00466. There are 0 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.3559-19delC		intron	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.2023-19delC		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.2020-19delC		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.3559-19delC		intron	N/A	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*2460-19delC		intron	N/A	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000460696.1	TSL:1	n.624-19delC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 439 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00252 AC: 508 AN: 201376 AF XY: 0.00266

Gnomad AFR exome AF: 0.000708

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.000762

Gnomad EAS exome AF: 0.0000691

Gnomad FIN exome AF: 0.000481

Gnomad NFE exome AF: 0.00441

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00405 AC: 5410 AN: 1337346 Hom.: 17 Cov.: 20 AF XY: 0.00392 AC XY: 2620 AN XY: 668128

African (AFR) AF: 0.000701 AC: 22 AN: 31396

American (AMR) AF: 0.00280 AC: 114 AN: 40738

Ashkenazi Jewish (ASJ) AF: 0.000560 AC: 14 AN: 25010

East Asian (EAS) AF: 0.0000265 AC: 1 AN: 37794

South Asian (SAS) AF: 0.000275 AC: 22 AN: 80004

European-Finnish (FIN) AF: 0.000292 AC: 15 AN: 51326

Middle Eastern (MID) AF: 0.00144 AC: 8 AN: 5566

European-Non Finnish (NFE) AF: 0.00501 AC: 5056 AN: 1009350

Other (OTH) AF: 0.00281 AC: 158 AN: 56162

GnomAD4 genome AF: 0.00287 AC: 438 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00303 AC XY: 226 AN XY: 74498

African (AFR) AF: 0.000794 AC: 33 AN: 41582

American (AMR) AF: 0.00562 AC: 86 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00429 AC: 292 AN: 68030

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00341

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs201335783;

hg19: chr1-5926536;