rs104894879

chrX-43958608-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000266.4(NDP):c.38T>G(p.Leu13Arg) 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).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NDP NM_000266.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.95

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant X-43958608-A-C is Pathogenic according to our data. Variant chrX-43958608-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 10689.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-43958608-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4	c.38T>G	p.Leu13Arg	missense_variant	2/3	ENST00000642620.1
NDP-AS1	NR_046631.1	n.467-2177A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDP	ENST00000642620.1	c.38T>G	p.Leu13Arg	missense_variant	2/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1	n.467-2177A>C		intron_variant, non_coding_transcript_variant		3
NDP	ENST00000647044.1	c.38T>G	p.Leu13Arg	missense_variant	3/4			P1
NDP	ENST00000470584.1	n.218+110T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

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

Apr 01, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.70	T
Polyphen		0.99	D;D;D
Vest4		0.98
MutPred		0.82		Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);Gain of MoRF binding (P = 0.0052);
MVP		1.0
MPC		1.7
ClinPred		0.88	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.96

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: rs104894879; hg19: chrX-43817854;