X-43949932-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PM1PM5PP2BS2

The NM_000266.4(NDP):c.269G>A(p.Arg90His) variant causes a missense change. The variant allele was found at a frequency of 0.0000655 in 1,205,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000069 ( 0 hom. 19 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:2

Conservation

PhyloP100: 3.70

Publications

4 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: Uncertain_significance. The variant received 1 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-43949933-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 373948.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.

BS2

High AC in GnomAdExome4 at 76 XL,AD gene.

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.269G>A	p.Arg90His	missense	Exon 3 of 3	NP_000257.1
	NDP-AS1	NR_046631.1		n.201C>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.269G>A	p.Arg90His	missense	Exon 3 of 3	ENSP00000495972.1
NDP	ENST00000647044.1		c.269G>A	p.Arg90His	missense	Exon 4 of 4	ENSP00000495811.1
NDP-AS1	ENST00000435093.1	TSL:3	n.201C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111565

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000236

AC:

AN:

169831

AF XY:

0.00

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:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000695

AC:

AN:

1093622

Hom.:

Cov.:

AF XY:

0.0000528

AC XY:

AN XY:

359720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26322

American (AMR)

AF:

0.00

AC:

AN:

34846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19283

East Asian (EAS)

AF:

0.0000333

AC:

AN:

30005

South Asian (SAS)

AF:

0.00

AC:

AN:

53056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40169

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4111

European-Non Finnish (NFE)

AF:

0.0000857

AC:

AN:

839912

Other (OTH)

AF:

0.0000653

AC:

AN:

45918

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

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111565

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33755

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30695

American (AMR)

AF:

0.00

AC:

AN:

10528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3513

South Asian (SAS)

AF:

0.00

AC:

AN:

2658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6021

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53087

Other (OTH)

AF:

0.00

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Atrophia bulborum hereditaria (1)

Hearing impairment (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

0.55

PhyloP100

3.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.86

REVEL

Uncertain

0.41

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.031

Polyphen

1.0

Vest4

0.17

MVP

0.93

MPC

1.6

ClinPred

0.38

GERP RS

6.0

Varity_R

0.56

gMVP

0.87

Mutation Taster

=27/73

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over