Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000266.4(NDP):c.179T>A(p.Val60Glu) 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).

Frequency

Genomes: not found (cov: 22)

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.90

Publications

7 publications found

Variant links:

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 links:

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

NDP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 9 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, 0.97

PP5

Variant X-43950022-A-T is Pathogenic according to our data. Variant chrX-43950022-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10681.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.179T>A	p.Val60Glu	missense	Exon 3 of 3	NP_000257.1
	NDP-AS1	NR_046631.1		n.291A>T		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NDP	ENST00000642620.1	MANE Select	c.179T>A	p.Val60Glu	missense	Exon 3 of 3	ENSP00000495972.1
NDP	ENST00000647044.1		c.179T>A	p.Val60Glu	missense	Exon 4 of 4	ENSP00000495811.1
NDP-AS1	ENST00000435093.1	TSL:3	n.291A>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Atrophia bulborum hereditaria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.77

MutationAssessor

Benign

0.90

PhyloP100

8.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.96

MutPred

0.82

Gain of helix (P = 0.005)

MVP

1.0

MPC

0.90

ClinPred

0.98

GERP RS

6.0

Varity_R

0.96

gMVP

1.0

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs104894869

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over