rs104894880

chrX-43950020-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000266.4(NDP):c.181C>T(p.Leu61Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L61I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.38

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 9 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant X-43950020-G-A is Pathogenic according to our data. Variant chrX-43950020-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10690.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-43950020-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.181C>T	p.Leu61Phe	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.289G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.181C>T	p.Leu61Phe	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.289G>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.181C>T	p.Leu61Phe	missense_variant	4/4			P1
NDP	ENST00000470584.1	n.225C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1083851 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 352161

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.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrophia bulborum hereditaria Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;D
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.90	L;L;L
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	D;D;D
Vest4		0.90
MutPred		0.79		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.98
MPC		0.98
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.87
gMVP		0.91

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: rs104894880; hg19: chrX-43809266;