X-43949817-G-C

Variant names:

• chrX-43949817-G-C
• NM_000266.4:c.384C>G

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.384C>G​(p.Cys128Trp) variant causes a missense change involving the alteration of a non-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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C128R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.256

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 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, 0.892
• PP5: Variant X-43949817-G-C is Pathogenic according to our data. Variant chrX-43949817-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3381811.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.384C>G	p.Cys128Trp	missense_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.86G>C		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.384C>G	p.Cys128Trp	missense_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.384C>G	p.Cys128Trp	missense_variant	Exon 4 of 4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.86G>C		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1	n.428C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal dystrophy Pathogenic:1

May 27, 2024

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.89	.;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-11	.;D;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.68		Loss of disorder (P = 0.0492);Loss of disorder (P = 0.0492);Loss of disorder (P = 0.0492);
MVP		1.0
MPC		1.7
ClinPred		0.99	D
GERP RS		-9.4
Varity_R		0.99
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-43809063;