X-43949861-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000266.4(NDP):c.339_340insC(p.Met114HisfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: NDP NM_000266.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.06

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. There are 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43949861-T-TG is Pathogenic according to our data. Variant chrX-43949861-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 2013719.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.339_340insC	p.Met114HisfsTer35	frameshift_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.131dup		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.339_340insC	p.Met114HisfsTer35	frameshift_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.131dup		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.339_340insC	p.Met114HisfsTer35	frameshift_variant	4/4			P1
NDP	ENST00000470584.1	n.383_384insC		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the NDP gene (p.Met114Hisfs*35). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the NDP protein and extend the protein by 14 additional amino acid residues. This variant has not been reported in the literature in individuals affected with NDP-related conditions. 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. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-43809107;