2-110163014-T-G

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.859+34A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,461,348 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (54 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.888

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=-0.84).
• BP6: Variant 2-110163014-T-G is Benign according to our data. Variant chr2-110163014-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 255704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-110163014-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2027/152222) while in subpopulation AFR AF= 0.0463 (1922/41510). AF 95% confidence interval is 0.0446. There are 48 homozygotes in gnomad4. There are 962 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP1	NM_001128178.3	c.859+34A>C		intron_variant		ENST00000445609.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP1	ENST00000445609.7	c.859+34A>C		intron_variant		1	NM_001128178.3	P2

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2019 AN: 152104 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00374 AC: 931 AN: 248962 Hom.: 25 AF XY: 0.00284 AC XY: 382 AN XY: 134408

Gnomad AFR exome AF: 0.0492

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00156 AC: 2048 AN: 1309126 Hom.: 54 Cov.: 19 AF XY: 0.00134 AC XY: 883 AN XY: 659388

Gnomad4 AFR exome AF: 0.0500

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000153

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.0133 AC: 2027 AN: 152222 Hom.: 48 Cov.: 32 AF XY: 0.0129 AC XY: 962 AN XY: 74438

Gnomad4 AFR AF: 0.0463

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00715 Hom.: 5

Bravo AF: 0.0154

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	4.5
Dann	Benign	0.55

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: rs79943015; hg19: chr2-110920591;