rs104894867

chrX-43949932-C-AchrX-43949932-C-GchrX-43949932-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000266.4(NDP):c.269G>T(p.Arg90Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,621 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 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-43949933-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373948.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.269G>T	p.Arg90Leu	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.201C>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.269G>T	p.Arg90Leu	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.201C>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.269G>T	p.Arg90Leu	missense_variant	4/4			P1
NDP	ENST00000470584.1	n.313G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000118 AC: 2 AN: 169831 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 56509

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000138

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000583

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093621 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 359719

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
Polyphen		0.96	D;D;D
Vest4		0.60
MutPred		0.34		Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);
MVP		0.95
MPC		1.6
ClinPred		0.55	D
GERP RS		6.0
Varity_R		0.73
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894867; hg19: chrX-43809178;