rs17463266

Variant names:

• chr2-110200752-C-T
• rs17463266
• NM_001128178.3:c.143+669G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128178.3(NPHP1):​c.143+669G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0699 in 152,102 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.070 (559 hom., cov: 33)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• Publications: 7 publications found

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.143+669G>A		intron_variant	Intron 2 of 19	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.143+669G>A		intron_variant	Intron 2 of 19	1	NM_001128178.3	ENSP00000389879.3

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10630 AN: 151984 Hom.: 559 Cov.: 33

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.0657

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0972

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0699 AC: 10628 AN: 152102 Hom.: 559 Cov.: 33 AF XY: 0.0681 AC XY: 5061 AN XY: 74352

African (AFR) AF: 0.0242 AC: 1004 AN: 41488

American (AMR) AF: 0.0704 AC: 1076 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 599 AN: 3468

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4810

European-Finnish (FIN) AF: 0.0657 AC: 695 AN: 10576

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.100 AC: 6803 AN: 67992

Other (OTH) AF: 0.0962 AC: 203 AN: 2110

Alfa AF: 0.0946 Hom.: 1321

Bravo AF: 0.0695

Asia WGS AF: 0.0130 AC: 46 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.5
DANN	Benign	0.62
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17463266; hg19: chr2-110958329;