X-43949855-G-A

Variant summary

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

The NM_000266.4(NDP):c.346C>T(p.Leu116Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000185 in 1,078,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000019 (0 hom. 1 hem.)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000266.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.346C>T	p.Leu116Phe	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.124G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.346C>T	p.Leu116Phe	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.124G>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.346C>T	p.Leu116Phe	missense_variant	4/4			P1
NDP	ENST00000470584.1	n.390C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000690 AC: 1 AN: 144865 Hom.: 0 AF XY: 0.0000225 AC XY: 1 AN XY: 44543

Gnomad AFR exome AF: 0.00

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: 0.0000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000185 AC: 2 AN: 1078178 Hom.: 0 Cov.: 30 AF XY: 0.00000284 AC XY: 1 AN XY: 351546

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: 0.00000240

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

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

Invitae

Nov 13, 2022

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. 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. This variant has not been reported in the literature in individuals affected with NDP-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 116 of the NDP protein (p.Leu116Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
Polyphen		0.92	P;P;P
Vest4		0.31
MutPred		0.25		Loss of catalytic residue at M114 (P = 0.0154);Loss of catalytic residue at M114 (P = 0.0154);Loss of catalytic residue at M114 (P = 0.0154);
MVP		0.83
MPC		1.1
ClinPred		0.56	D
GERP RS		6.0
Varity_R		0.68
gMVP		0.94

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: rs1302861734; hg19: chrX-43809101;