rs112090979

Positions:

• chr2-110143523-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128178.3(NPHP1):​c.1529+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,554,506 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.013 (183 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0740

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=-0.85).
• BP6: Variant 2-110143523-G-A is Benign according to our data. Variant chr2-110143523-G-A is described in ClinVar as [Benign]. Clinvar id is 255708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-110143523-G-A is described in Lovd as [Likely_benign]. Variant chr2-110143523-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1622/152258) while in subpopulation NFE AF= 0.0156 (1059/68016). AF 95% confidence interval is 0.0148. There are 22 homozygotes in gnomad4. There are 812 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP1	NM_001128178.3	c.1529+19C>T		intron_variant		ENST00000445609.7	NP_001121650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP1	ENST00000445609.7	c.1529+19C>T		intron_variant		1	NM_001128178.3	ENSP00000389879	P2

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1622 AN: 152140 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0107 AC: 2696 AN: 251228 Hom.: 39 AF XY: 0.0107 AC XY: 1459 AN XY: 135790

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0134 AC: 18796 AN: 1402248 Hom.: 183 Cov.: 24 AF XY: 0.0131 AC XY: 9176 AN XY: 701286

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00656

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000963

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0107 AC: 1622 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74442

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0125 Hom.: 3

Bravo AF: 0.00946

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.38

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: rs112090979; hg19: chr2-110901100;