rs1509419

chr2-110144616-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001128178.3(NPHP1):c.1353-47T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,111,680 control chromosomes in the GnomAD database, including 2,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (1319 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (881 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.414

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-110144616-A-G is Benign according to our data. Variant chr2-110144616-A-G is described in ClinVar as [Benign]. Clinvar id is 255707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP1	NM_001128178.3	c.1353-47T>C		intron_variant		ENST00000445609.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP1	ENST00000445609.7	c.1353-47T>C		intron_variant		1	NM_001128178.3	P2

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11087 AN: 152134 Hom.: 1317 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.0637

GnomAD3 exomes AF: 0.0200 AC: 4896 AN: 245254 Hom.: 527 AF XY: 0.0150 AC XY: 1996 AN XY: 132778

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000632

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00954 AC: 9150 AN: 959428 Hom.: 881 Cov.: 14 AF XY: 0.00802 AC XY: 4008 AN XY: 499640

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000670

Gnomad4 FIN exome AF: 0.000586

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0730 AC: 11109 AN: 152252 Hom.: 1319 Cov.: 32 AF XY: 0.0707 AC XY: 5264 AN XY: 74452

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.0304

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0355 Hom.: 163

Bravo AF: 0.0822

Asia WGS AF: 0.0160 AC: 55 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.19
Dann	Benign	0.42

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: rs1509419; hg19: chr2-110902193;