chrX-43949981-G-T

Variant names:

• chrX-43949981-G-T
• rs727504031
• NM_000266.4:c.220C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_000266.4(NDP):​c.220C>A​(p.Arg74Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55
• Publications: 0 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 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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-43949981-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 167326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4	c.220C>A	p.Arg74Ser	missense_variant	Exon 3 of 3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.250G>T		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.220C>A	p.Arg74Ser	missense_variant	Exon 3 of 3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.220C>A	p.Arg74Ser	missense_variant	Exon 4 of 4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.250G>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1	n.264C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg74 amino acid residue in NDP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1307245, 15776010, 22563645, 23141577). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals affected with NDP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 74 of the NDP protein (p.Arg74Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;L;L
PhyloP100		9.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	.;N;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	.;D;.
Sift4G	Benign	0.086	.;T;.
Polyphen		1.0	D;D;D
Vest4		0.73
MutPred		0.23		Gain of phosphorylation at R74 (P = 0.0399);Gain of phosphorylation at R74 (P = 0.0399);Gain of phosphorylation at R74 (P = 0.0399);
MVP		1.0
MPC		0.66
ClinPred		0.81	D
GERP RS		6.0
Varity_R		0.98
gMVP		0.96
Mutation Taster		=9/91	disease causing

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: rs727504031; hg19: chrX-43809227;