3-132682824-TAAAAA-TAAAA

Position:

• chr3-132682824-TAAAAA-TAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_153240.5(NPHP3):​c.3697-7delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,557,810 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (9 hom.)
• Consequence: NPHP3 NM_153240.5 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.497

Genes affected

NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

NPHP3-ACAD11 (HGNC:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

NPHP3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 3-132682824-TA-T is Benign according to our data. Variant chr3-132682824-TA-T is described in ClinVar as [Benign]. Clinvar id is 422589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-132682824-TA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000664 (101/152110) while in subpopulation EAS AF= 0.0129 (67/5190). AF 95% confidence interval is 0.0104. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.3697-7delT		splice_region_variant, intron_variant		ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.3703-7delT		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.3697-7delT		splice_region_variant, intron_variant		1	NM_153240.5	ENSP00000338766.5
NPHP3-ACAD11	ENST00000632629.1	c.343-7delT		splice_region_variant, intron_variant		2		ENSP00000488520.1

Frequencies

GnomAD3 genomes AF: 0.000665 AC: 101 AN: 151992 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00155 AC: 388 AN: 250424 Hom.: 4 AF XY: 0.00169 AC XY: 229 AN XY: 135368

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0158

Gnomad SAS exome AF: 0.000983

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.000433

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000716 AC: 1007 AN: 1405700 Hom.: 9 Cov.: 24 AF XY: 0.000777 AC XY: 546 AN XY: 702600

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.0157

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.000581

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.000701

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.000740 AC XY: 55 AN XY: 74354

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0129

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000782

Asia WGS AF: 0.00780 AC: 27 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000475

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NPHP3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs564013823; hg19: chr3-132401668;