Variant X-43958512-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000266.4(NDP):c.134T>A(p.Val45Glu) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.74

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 made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a domain CTCK (size 93) in uniprot entity NDP_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

PP5

Variant X-43958512-A-T is Pathogenic according to our data. Variant chrX-43958512-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 10697.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-43958512-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4 linkuse as main transcript	c.134T>A	p.Val45Glu	missense_variant	2/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1 linkuse as main transcript	n.467-2273A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NDP	ENST00000642620.1 linkuse as main transcript	c.134T>A	p.Val45Glu	missense_variant	2/3		NM_000266.4	ENSP00000495972	P1
NDP-AS1	ENST00000435093.1 linkuse as main transcript	n.467-2273A>T		intron_variant, non_coding_transcript_variant		3
NDP	ENST00000647044.1 linkuse as main transcript	c.134T>A	p.Val45Glu	missense_variant	3/4			ENSP00000495811	P1
NDP	ENST00000470584.1 linkuse as main transcript	n.218+206T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Atrophia bulborum hereditaria

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.67

BayesDel_noAF

Pathogenic

0.72

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D;D

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

.;.;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.97

L;L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.31

.;N;.

REVEL

Pathogenic

0.76

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;D

Vest4

0.95

MutPred

0.78

Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);Gain of solvent accessibility (P = 0.0058);

MVP

1.0

MPC

1.8

ClinPred

0.83

GERP RS

6.0

Varity_R

0.95

gMVP

0.95

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over