rs3789735

Positions:

• chr2-110128565-G-A
• chr2-110128565-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128178.3(NPHP1):​c.1716+621C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 153,516 control chromosomes in the GnomAD database, including 8,132 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 0.31 (8046 hom., cov: 32)
  • Exomes 𝑓: 0.30 (86 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP1	NM_001128178.3	c.1716+621C>T		intron_variant		ENST00000445609.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP1	ENST00000445609.7	c.1716+621C>T		intron_variant		1	NM_001128178.3	P2

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47448 AN: 151866 Hom.: 8023 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.304 AC: 465 AN: 1532 Hom.: 86 Cov.: 0 AF XY: 0.314 AC XY: 258 AN XY: 822

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.536

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.281

Gnomad4 OTH exome AF: 0.353

GnomAD4 genome AF: 0.313 AC: 47526 AN: 151984 Hom.: 8046 Cov.: 32 AF XY: 0.317 AC XY: 23539 AN XY: 74288

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.576

Gnomad4 SAS AF: 0.499

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.316

Alfa AF: 0.324 Hom.: 4684

Bravo AF: 0.317

Asia WGS AF: 0.501 AC: 1741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs3789735; hg19: chr2-110886142;