2-110123452-GGTT-G

Position:

• chr2-110123452-GGTT-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001128178.3(NPHP1):​c.*336_*338del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 203,890 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (1 hom.)
• Consequence: NPHP1 NM_001128178.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.0370

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00132 (200/151876) while in subpopulation SAS AF= 0.00459 (22/4798). AF 95% confidence interval is 0.0031. There are 2 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.*336_*338del		3_prime_UTR_variant	20/20	ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.*336_*338del		3_prime_UTR_variant	20/20	1	NM_001128178.3	ENSP00000389879	P2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 200 AN: 151758 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00458

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00183

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00181 AC: 94 AN: 52014 Hom.: 1 AF XY: 0.00202 AC XY: 57 AN XY: 28254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00235

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00485

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.00132 AC: 200 AN: 151876 Hom.: 2 Cov.: 33 AF XY: 0.00148 AC XY: 110 AN XY: 74216

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00459

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.00183

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00125

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Renal dysplasia and retinal aplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs555468187; hg19: chr2-110881029;