rs137852221

Variant names:

• chrX-43958512-A-T
• rs137852221
• NM_000266.4:c.134T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000266.4(NDP):​c.134T>A​(p.Val45Glu) variant causes a missense change involving the alteration of a 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.74
• Publications: 7 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000266.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Norrie disease, exudative vitreoretinopathy 2, X-linked, exudative vitreoretinopathy, persistent hyperplastic primary vitreous.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant X-43958512-A-T is Pathogenic according to our data. Variant chrX-43958512-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10697.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.134T>A	p.Val45Glu	missense_variant	Exon 2 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.467-2273A>T		intron_variant	Intron 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.134T>A	p.Val45Glu	missense_variant	Exon 2 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.134T>A	p.Val45Glu	missense_variant	Exon 3 of 4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.467-2273A>T		intron_variant	Intron 3 of 4	3
NDP	ENST00000470584.1	n.218+206T>A		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrophia bulborum hereditaria Pathogenic:1

May 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.97	L;L;L
PhyloP100		8.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.31	.;N;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.78		Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);
MVP		1.0
MPC		1.8
ClinPred		0.83	D
GERP RS		6.0
Varity_R		0.95
gMVP		0.95
Mutation Taster		=5/95	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: rs137852221; hg19: chrX-43817758;