Genetic Variant NDP:p.Ser75Phe (chrX-43949977-G-A) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_000266.4(NDP):c.224C>T(p.Ser75Phe) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S75C) has been classified 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 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.55

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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, 7 uncertain in NM_000266.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-43949977-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 10680.Status of the report is criteria_provided_single_submitter, 1 stars.

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, 0.893

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.224C>T	p.Ser75Phe	missense	Exon 3 of 3	NP_000257.1
	NDP-AS1	NR_046631.1		n.246G>A		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.224C>T	p.Ser75Phe	missense	Exon 3 of 3	ENSP00000495972.1
NDP	ENST00000647044.1		c.224C>T	p.Ser75Phe	missense	Exon 4 of 4	ENSP00000495811.1
NDP-AS1	ENST00000435093.1	TSL:3	n.246G>A		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1094447

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360341

African (AFR)

AF:

0.00

AC:

AN:

26341

American (AMR)

AF:

0.00

AC:

AN:

34899

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19308

East Asian (EAS)

AF:

0.00

AC:

AN:

30052

South Asian (SAS)

AF:

0.00

AC:

AN:

53173

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40227

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4103

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840416

Other (OTH)

AF:

0.00

AC:

AN:

45928

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.65

BayesDel_noAF

Pathogenic

0.70

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

0.81

PhyloP100

9.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

1.4

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.68

MutPred

0.39

Loss of relative solvent accessibility (P = 0.008)

MVP

0.99

MPC

0.82

ClinPred

0.69

GERP RS

6.0

Varity_R

0.95

gMVP

0.95

Mutation Taster

=16/84

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over