rs104894878

chrX-43949840-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000266.4(NDP):c.361C>T(p.Arg121Trp) variant causes a missense change. 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. R121L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.11

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 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000266.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-43949839-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 10695.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant X-43949840-G-A is Pathogenic according to our data. Variant chrX-43949840-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-43949840-G-A is described in Lovd as [Pathogenic]. Variant chrX-43949840-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.361C>T	p.Arg121Trp	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.109G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.361C>T	p.Arg121Trp	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.109G>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.361C>T	p.Arg121Trp	missense_variant	4/4			P1
NDP	ENST00000470584.1	n.405C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1073891 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 350053

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2015	The R121W variant in the NDP gene has been reported previously in association with X-linked familial exudative vitreoretinopathy (Meindl et al., 1995; Pelcastre et al., 2010; Fuchs et al., 1995; Wu et al., 2007). The R121W variant was not observed in approximately 6,488 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R121W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information R121W is interpreted to be a likely pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 06, 2021	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects NDP protein function (PMID: 26158506). This variant has been observed in individual(s) with exudative vitreoretinopathy (PMID: 7795608, 17296899, 20491809, 8832723, 7558002). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10688). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 121 of the NDP protein (p.Arg121Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Exudative vitreoretinopathy 2, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Atrophia bulborum hereditaria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Jul 12, 2023

ACMG criteria used to clasify this variant: PS4_MOD, PP3_MOD, PM2_SUP, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.78	T
Polyphen		1.0	D;D;D
Vest4		0.85
MutPred		0.90		Loss of disorder (P = 0.0027);Loss of disorder (P = 0.0027);Loss of disorder (P = 0.0027);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.96

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: rs104894878; hg19: chrX-43809086;