X-43949808-G-T

Variant names:

• chrX-43949808-G-T
• rs2035749589
• NM_000266.4:c.393C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000266.4(NDP):​c.393C>A​(p.Cys131*) variant causes a stop gained change. 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 Likely 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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.65

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 Likely_pathogenic. Variant got 6 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 0.0224 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43949808-G-T is Pathogenic according to our data. Variant chrX-43949808-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 962350.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-43949808-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.393C>A	p.Cys131*	stop_gained	Exon 3 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.77G>T		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.393C>A	p.Cys131*	stop_gained	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.393C>A	p.Cys131*	stop_gained	Exon 4 of 4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.77G>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1	n.437C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1058790 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 343884

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts a region of the protein in which other variant(s) (p.Ser133Cys) have been observed in individuals with NDP-related conditions (PMID: 29633608). This suggests that this may be a clinically significant region of the NDP protein. This variant has been observed in individuals affected with clinical features of familial exudative vitreoretinopathy (PMID: 25711638, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the NDP gene (p.Cys131*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acids of the NDP protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.82
GERP RS		3.1

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: rs2035749589; hg19: chrX-43809054;