X-43949914-C-T

Position:

• chrX-43949914-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000266.4(NDP):​c.287G>A​(p.Cys96Tyr) 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).

• Frequency: Genomes: not found (cov: 22)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.54

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:40395): (NDP antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a disulfide_bond (size 59) in uniprot entity NDP_HUMAN there are 21 pathogenic changes around while only 0 benign (100%) in NM_000266.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant X-43949914-C-T is Pathogenic according to our data. Variant chrX-43949914-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10683.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-43949914-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.287G>A	p.Cys96Tyr	missense_variant	3/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.183C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.287G>A	p.Cys96Tyr	missense_variant	3/3		NM_000266.4	ENSP00000495972	P1
NDP-AS1	ENST00000435093.1	n.183C>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.287G>A	p.Cys96Tyr	missense_variant	4/4			ENSP00000495811	P1
NDP	ENST00000470584.1	n.331G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrophia bulborum hereditaria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-11	.;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.83		Gain of MoRF binding (P = 0.0697);Gain of MoRF binding (P = 0.0697);Gain of MoRF binding (P = 0.0697);
MVP		1.0
MPC		1.8
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.97
gMVP		1.0

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: rs104894871; hg19: chrX-43809160;