NM_153240.5:c.60C>G

Variant names:

• chr3-132722296-G-C
• rs773521620
• NM_153240.5:c.60C>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_153240.5(NPHP3):​c.60C>G​(p.Tyr20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,427,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y20Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NPHP3 NM_153240.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.229
• Publications: 0 publications found

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-AS1 (HGNC:24129): (NPHP3 antisense RNA 1)

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]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 127 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-132722296-G-C is Pathogenic according to our data. Variant chr3-132722296-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 462730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.60C>G	p.Tyr20*	stop_gained	Exon 1 of 27	ENST00000337331.10	NP_694972.3
NPHP3-AS1	NR_002811.2	n.547G>C		non_coding_transcript_exon_variant	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1	n.164C>G		non_coding_transcript_exon_variant	Exon 1 of 45
NPHP3-AS1	NR_152743.1	n.547G>C		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.60C>G	p.Tyr20*	stop_gained	Exon 1 of 27	1	NM_153240.5	ENSP00000338766.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000175 AC: 25 AN: 1427772 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 10 AN XY: 710738

African (AFR) AF: 0.00 AC: 0 AN: 30936

American (AMR) AF: 0.00 AC: 0 AN: 42944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37442

South Asian (SAS) AF: 0.00 AC: 0 AN: 84120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5022

European-Non Finnish (NFE) AF: 0.0000208 AC: 23 AN: 1104060

Other (OTH) AF: 0.0000337 AC: 2 AN: 59410

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Nephronophthisis Pathogenic:1

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 462730). This variant has not been reported in the literature in individuals affected with NPHP3-related conditions. This sequence change creates a premature translational stop signal (p.Tyr20*) in the NPHP3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPHP3 are known to be pathogenic (PMID: 18371931, 23559409). -

not provided Pathogenic:1

Mar 26, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.45	N
PhyloP100		-0.23
Vest4		0.76
GERP RS		1.7
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs773521620; hg19: chr3-132441140;