rs1460859456

Positions:

• chrX-43950001-C-A
• chrX-43950001-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000266.4(NDP):​c.200G>T​(p.Gly67Val) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G67E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.53

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-AS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Norrin (size 108) in uniprot entity NDP_HUMAN there are 39 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, 0.91
• PP5: Variant X-43950001-C-A is Pathogenic according to our data. Variant chrX-43950001-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.200G>T	p.Gly67Val	missense_variant	3/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.270C>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.200G>T	p.Gly67Val	missense_variant	3/3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.200G>T	p.Gly67Val	missense_variant	4/4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.270C>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1	n.244G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Exudative vitreoretinopathy 2, X-linked Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.8	.;D;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.022	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.36		Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);Gain of sheet (P = 0.0016);
MVP		1.0
MPC		0.94
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.99

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

Other links and lift over

dbSNP: rs1460859456; hg19: chrX-43809247;