NM_000266.4:c.343C>T

Variant names:

• chrX-43949858-G-A
• rs779079304
• NM_000266.4:c.343C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000266.4(NDP):​c.343C>T​(p.Arg115*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: NDP NM_000266.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.43
• Publications: 2 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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-43949858-G-A is Pathogenic according to our data. Variant chrX-43949858-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2737212.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	NM_000266.4	MANE Select	c.343C>T	p.Arg115*	stop_gained	Exon 3 of 3	NP_000257.1	Q00604
	NDP-AS1	NR_046631.1		n.127G>A		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDP	ENST00000642620.1	MANE Select	c.343C>T	p.Arg115*	stop_gained	Exon 3 of 3	ENSP00000495972.1	Q00604
	NDP	ENST00000647044.1		c.343C>T	p.Arg115*	stop_gained	Exon 4 of 4	ENSP00000495811.1	Q00604
	NDP	ENST00000868527.1		c.343C>T	p.Arg115*	stop_gained	Exon 3 of 3	ENSP00000538586.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1078628 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 351634

African (AFR) AF: 0.00 AC: 0 AN: 25982

American (AMR) AF: 0.00 AC: 0 AN: 32228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18972

East Asian (EAS) AF: 0.00 AC: 0 AN: 29109

South Asian (SAS) AF: 0.00 AC: 0 AN: 51385

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 832333

Other (OTH) AF: 0.00 AC: 0 AN: 45375

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		1.4
Vest4		0.90
GERP RS		4.0
Mutation Taster		=26/174	disease causing

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: rs779079304; hg19: chrX-43809104;