Genetic Variant NDP:p.Arg74Ser (chrX-43949981-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_000266.4(NDP):c.220C>A(p.Arg74Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.55

Publications

0 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 8 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-43949981-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 167326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.835

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.220C>A	p.Arg74Ser	missense	Exon 3 of 3	NP_000257.1
	NDP-AS1	NR_046631.1		n.250G>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.220C>A	p.Arg74Ser	missense	Exon 3 of 3	ENSP00000495972.1
NDP	ENST00000647044.1		c.220C>A	p.Arg74Ser	missense	Exon 4 of 4	ENSP00000495811.1
NDP	ENST00000868527.1		c.220C>A	p.Arg74Ser	missense	Exon 3 of 3	ENSP00000538586.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.90

PhyloP100

9.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Benign

0.086

Polyphen

1.0

Vest4

0.73

MutPred

0.23

Gain of phosphorylation at R74 (P = 0.0399)

MVP

1.0

MPC

0.66

ClinPred

0.81

GERP RS

6.0

Varity_R

0.98

gMVP

0.96

Mutation Taster

=9/91

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