rs104894874

Positions:

• chrX-43958521-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000266.4(NDP):​c.125A>G​(p.His42Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,884 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.50

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 14 ACMG points.

• PM1: In a domain CTCK (size 93) in uniprot entity NDP_HUMAN there are 37 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, 0.925
• PP5: Variant X-43958521-T-C is Pathogenic according to our data. Variant chrX-43958521-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-43958521-T-C is described in Lovd as [Pathogenic]. Variant chrX-43958521-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.125A>G	p.His42Arg	missense_variant	2/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.467-2264T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.125A>G	p.His42Arg	missense_variant	2/3		NM_000266.4	ENSP00000495972	P1
NDP-AS1	ENST00000435093.1	n.467-2264T>C		intron_variant, non_coding_transcript_variant		3
NDP	ENST00000647044.1	c.125A>G	p.His42Arg	missense_variant	3/4			ENSP00000495811	P1
NDP	ENST00000470584.1	n.218+197A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183259 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67771

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363356

Gnomad4 AFR exome AF: 0.0000379

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.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17296899, 17050281, 27720678, 9143917, 35328049, Santos2022[MeetingAbstract], 33781268) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2023	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 42 of the NDP protein (p.His42Arg). This variant is present in population databases (rs104894874, gnomAD 0.008%). This missense change has been observed in individuals with familial exudative vitreoretinopathy (PMID: 9143917, 17050281; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. For these reasons, this variant has been classified as Pathogenic. -

Atrophia bulborum hereditaria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 29, 2024

Variant summary: NDP c.125A>G (p.His42Arg) results in a non-conservative amino acid change located in the Cystine knot, C-terminal domain (IPR006207) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183259 control chromosomes. c.125A>G has been reported in the hemizygous state in the literature in multiple individuals affected with familial exudative vitreoretinopathy (FEVR) (examples: Cicerone_2022, Shastry_1997, Wu_2007). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35328049, 9143917, 17296899). ClinVar contains an entry for this variant (Variation ID: 10691). Based on the evidence outlined above, the variant was classified as pathogenic. -

Exudative vitreoretinopathy, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 08, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.66
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.019	.;D;.
Sift4G	Benign	0.093	.;T;.
Polyphen		0.99	D;D;D
Vest4		0.94
MutPred		0.76		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);
MVP		1.0
MPC		1.6
ClinPred		0.38	T
GERP RS		5.8
Varity_R		0.77
gMVP		0.95

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: rs104894874; hg19: chrX-43817767;