chrX-43949812-T-C

Position:

• chrX-43949812-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000266.4(NDP):​c.389A>G​(p.Glu130Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.389A>G	p.Glu130Gly	missense_variant	3/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.81T>C		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.389A>G	p.Glu130Gly	missense_variant	3/3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.389A>G	p.Glu130Gly	missense_variant	4/4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.81T>C		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1	n.433A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000786 AC: 1 AN: 127175 Hom.: 0 AF XY: 0.0000241 AC XY: 1 AN XY: 41559

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000481

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 Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 05, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 130 of the NDP protein (p.Glu130Gly). This variant is present in population databases (no rsID available, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with NDP-related conditions. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	.;.;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.81	L;L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	.;N;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.010	.;D;.
Sift4G	Uncertain	0.047	.;D;.
Polyphen		0.76	P;P;P
Vest4		0.45
MutPred		0.27		Loss of solvent accessibility (P = 0.0387);Loss of solvent accessibility (P = 0.0387);Loss of solvent accessibility (P = 0.0387);
MVP		0.98
MPC		1.0
ClinPred		0.48	T
GERP RS		6.0
Varity_R		0.53
gMVP		0.93

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: rs1256956156; hg19: chrX-43809058;