chrX-43949851-G-GTGAGTCGCATGCCCCC

Variant names:

• chrX-43949851-G-GTGAGTCGCATGCCCCC
• NM_000266.4:c.334_349dupGGGGGCATGCGACTCA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_000266.4(NDP):​c.334_349dupGGGGGCATGCGACTCA​(p.Thr117ArgfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.64
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 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. There are 12 pathogenic variants in the truncated region.
• PP5: Variant X-43949851-G-GTGAGTCGCATGCCCCC is Pathogenic according to our data. Variant chrX-43949851-G-GTGAGTCGCATGCCCCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3382646.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.334_349dupGGGGGCATGCGACTCA	p.Thr117ArgfsTer37	frameshift_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.125_140dupTCGCATGCCCCCTGAG		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.334_349dupGGGGGCATGCGACTCA	p.Thr117ArgfsTer37	frameshift_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.334_349dupGGGGGCATGCGACTCA	p.Thr117ArgfsTer37	frameshift_variant	Exon 4 of 4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.125_140dupTCGCATGCCCCCTGAG		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1	n.378_393dupGGGGGCATGCGACTCA		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrophia bulborum hereditaria;C1844579:Exudative vitreoretinopathy 2, X-linked Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Strong+PM2_Supporting+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6

Splicing

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

Other links and lift over

hg19: chrX-43809097;