rs1057518836

chrX-43949887-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000266.4(NDP):c.314C>T(p.Ala105Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A105T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.56

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 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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-43949888-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10693.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant X-43949887-G-A is Pathogenic according to our data. Variant chrX-43949887-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374014.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.314C>T	p.Ala105Val	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.156G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.314C>T	p.Ala105Val	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.156G>A		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1	c.314C>T	p.Ala105Val	missense_variant	4/4			P1
NDP	ENST00000470584.1	n.358C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nystagmus;C0266568:Persistent hyperplastic primary vitreous;C0271183:High myopia;C0426501:Short lingual frenulum Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 03, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;D;D
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.97	L;L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
Polyphen		1.0	D;D;D
Vest4		0.76
MutPred		0.39		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP		0.99
MPC		1.4
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.91
gMVP		0.84

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: rs1057518836; hg19: chrX-43809133; COSMIC: COSV65203510;