Genetic Variant NM_000266.4:c.346C>T (chrX-43949855-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000266.4(NDP):c.346C>T(p.Leu116Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,078,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86

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: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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.

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.346C>T	p.Leu116Phe	missense	Exon 3 of 3	NP_000257.1	Q00604
	NDP-AS1	NR_046631.1		n.124G>A		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.346C>T	p.Leu116Phe	missense	Exon 3 of 3	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1		c.346C>T	p.Leu116Phe	missense	Exon 4 of 4	ENSP00000495811.1	Q00604
NDP	ENST00000868527.1		c.346C>T	p.Leu116Phe	missense	Exon 3 of 3	ENSP00000538586.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000690

AC:

AN:

144865

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000185

AC:

AN:

1078178

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

351546

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25997

American (AMR)

AF:

0.00

AC:

AN:

32092

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18957

East Asian (EAS)

AF:

0.00

AC:

AN:

29065

South Asian (SAS)

AF:

0.00

AC:

AN:

51329

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.00000240

AC:

AN:

832131

Other (OTH)

AF:

0.00

AC:

AN:

45370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

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

0.59

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.52

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.55

PhyloP100

4.9

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.36

Sift

Uncertain

0.017

Sift4G

Benign

0.072

Polyphen

0.92

Vest4

0.31

MutPred

0.25

Loss of catalytic residue at M114 (P = 0.0154)

MVP

0.83

MPC

1.1

ClinPred

0.56

GERP RS

6.0

Varity_R

0.68

gMVP

0.94

Mutation Taster

=71/29

polymorphism

(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.

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