Variant X-43949839-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate

The NM_000266.4(NDP):c.362G>A(p.Arg121Gln) 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.54

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 14 ACMG points.

PS1

Transcript NM_000266.4 (NDP) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a disulfide_bond (size 61) in uniprot entity NDP_HUMAN there are 24 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, 0.954

PP5

Variant X-43949839-C-T is Pathogenic according to our data. Variant chrX-43949839-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3249058.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-43949839-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-43949839-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.362G>A	p.Arg121Gln	missense_variant	3/3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.108C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NDP	ENST00000642620.1 link	c.362G>A	p.Arg121Gln	missense_variant	3/3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.362G>A	p.Arg121Gln	missense_variant	4/4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.108C>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1 link	n.406G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1073359

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

349797

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;D;D

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

.;.;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

0.97

L;L;L

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.8

.;D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

1.0

D;D;D

Vest4

0.89

MutPred

0.79

Loss of MoRF binding (P = 0.0403);Loss of MoRF binding (P = 0.0403);Loss of MoRF binding (P = 0.0403);

MVP

1.0

MPC

1.5

ClinPred

1.0

GERP RS

6.0

Varity_R

0.96

gMVP

0.93

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over