NM_000266.4:c.269G>C

Variant names:

• chrX-43949932-C-G
• rs104894867
• NM_000266.4:c.269G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_000266.4(NDP):​c.269G>C​(p.Arg90Pro) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.70
• Publications: 4 publications found

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

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 chrX-43949933-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 373948.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Norrie disease, exudative vitreoretinopathy 2, X-linked, exudative vitreoretinopathy, persistent hyperplastic primary vitreous.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 3 of 3	NP_000257.1	Q00604
	NDP-AS1	NR_046631.1		n.201C>G		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	ENST00000642620.1	MANE Select	c.269G>C	p.Arg90Pro	missense	Exon 3 of 3	ENSP00000495972.1	Q00604
	NDP	ENST00000647044.1		c.269G>C	p.Arg90Pro	missense	Exon 4 of 4	ENSP00000495811.1	Q00604
	NDP	ENST00000868527.1		c.269G>C	p.Arg90Pro	missense	Exon 3 of 3	ENSP00000538586.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Atrophia bulborum hereditaria (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.55	N
PhyloP100		3.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.73		Loss of MoRF binding (P = 0.0058)
MVP		1.0
MPC		1.7
ClinPred		0.89	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894867; hg19: chrX-43809178;