X-43949836-T-C

Position:

• chrX-43949836-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000266.4(NDP):​c.365A>G​(p.Tyr122Cys) 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 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: 7.64

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 disulfide_bond (size 61) in uniprot entity NDP_HUMAN there are 24 pathogenic changes around while only 0 benign (100%) in NM_000266.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.365A>G	p.Tyr122Cys	missense_variant	3/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.105T>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.365A>G	p.Tyr122Cys	missense_variant	3/3		NM_000266.4	ENSP00000495972.1
NDP	ENST00000647044.1	c.365A>G	p.Tyr122Cys	missense_variant	4/4			ENSP00000495811.1
NDP-AS1	ENST00000435093.1	n.105T>C		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000470584.1	n.409A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

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

Eurofins Ntd Llc (ga)

Feb 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.97	L;L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.3	.;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;D
Vest4		0.79
MutPred		0.63		Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.97
gMVP		0.98

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: rs794727478; hg19: chrX-43809082;