Genetic Variant NM_000266.4:c.368T>A (chrX-43949833-A-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_000266.4(NDP):c.368T>A(p.Ile123Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,071,578 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 1 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.91

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: Pathogenic. The variant received 11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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, 0.977

PP5

Variant X-43949833-A-T is Pathogenic according to our data. Variant chrX-43949833-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2737210.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.368T>A	p.Ile123Asn	missense	Exon 3 of 3	NP_000257.1	Q00604
	NDP-AS1	NR_046631.1		n.102A>T		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDP	ENST00000642620.1	MANE Select	c.368T>A	p.Ile123Asn	missense	Exon 3 of 3	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1		c.368T>A	p.Ile123Asn	missense	Exon 4 of 4	ENSP00000495811.1	Q00604
NDP	ENST00000868527.1		c.368T>A	p.Ile123Asn	missense	Exon 3 of 3	ENSP00000538586.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.33e-7

AC:

AN:

1071578

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

349288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25790

American (AMR)

AF:

0.00

AC:

AN:

30782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18856

East Asian (EAS)

AF:

0.00

AC:

AN:

28635

South Asian (SAS)

AF:

0.00

AC:

AN:

50844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

828630

Other (OTH)

AF:

0.00

AC:

AN:

45151

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

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

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

0.97

PhyloP100

8.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.84

Gain of disorder (P = 0.0014)

MVP

0.98

MPC

1.9

ClinPred

1.0

GERP RS

6.0

Varity_R

0.98

gMVP

0.99

Mutation Taster

=6/94

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