X-43958645-T-C

Variant names:

• chrX-43958645-T-C
• rs28933685
• NM_000266.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000266.4(NDP):​c.1A>G​(p.Met1?) variant causes a start lost 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 (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: NDP NM_000266.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.42
• Publications: 6 publications found

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

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 12 codons. Genomic position: 43958612. Lost 0.085 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43958645-T-C is Pathogenic according to our data. Variant chrX-43958645-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 10687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000266.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 2 of 3	NP_000257.1
	NDP-AS1	NR_046631.1		n.467-2140T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	ENST00000642620.1	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 2 of 3	ENSP00000495972.1
	NDP	ENST00000647044.1		c.1A>G	p.Met1?	start_lost	Exon 3 of 4	ENSP00000495811.1
	NDP-AS1	ENST00000435093.1	TSL:3	n.467-2140T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Atrophia bulborum hereditaria (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		5.4
PROVEAN	Benign	-0.55	N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.82
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0199)
MVP		1.0
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.55
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28933685; hg19: chrX-43817891;