X-43949817-G-T

Position:

• chrX-43949817-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000266.4(NDP):​c.384C>A​(p.Cys128*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NDP NM_000266.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.256

Genes affected

NDP (HGNC:7678): (norrin cystine knot growth factor NDP) This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy. [provided by RefSeq, Feb 2009]

NDP-AS1 (HGNC:40395): (NDP antisense RNA 1)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0448 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43949817-G-T is Pathogenic according to our data. Variant chrX-43949817-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-43949817-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.384C>A	p.Cys128*	stop_gained	3/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.86G>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.384C>A	p.Cys128*	stop_gained	3/3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.384C>A	p.Cys128*	stop_gained	4/4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.86G>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1	n.428C>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1064123 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346527

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NDP protein in which other variant(s) (p.Cys131*) have been determined to be pathogenic (PMID: 25711638; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 10686). This variant is also known as C792A (Cys128stp). This premature translational stop signal has been observed in individuals with Norrie disease (PMID: 7627181, 8240113). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys128*) in the NDP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the NDP protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2015	The C128X nonsense variant in the NDP gene has been reported previously in association with Norriedisease (Wong et al., 1993; Schuback et al., 1995). This variant is predicted to cause loss of normal protein function through protein truncation. Therefore, we interpret this variant as pathogenic. -

Atrophia bulborum hereditaria Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1993	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine, University of Pavia	Jul 28, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Benign	0.93
FATHMM_MKL	Benign	0.31	N
Vest4		0.89
GERP RS		-9.4

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: rs104894873; hg19: chrX-43809063;