Genetic Variant NDP:p.Glu129* (chrX-43949816-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_000266.4(NDP):c.385G>T(p.Glu129*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000094 in 1,064,336 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E129E) has been classified as Benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

NDP
NM_000266.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.54

Publications

2 publications found

Variant links:

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 links:

NDP-AS1 (HGNC:40395): (NDP antisense RNA 1)

NDP-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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. Fraction of 0.0423 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDP	NM_000266.4 link	c.385G>T	p.Glu129*	stop_gained	Exon 3 of 3	ENST00000642620.1	NP_000257.1	Q00604
NDP-AS1	NR_046631.1 link	n.85C>A		non_coding_transcript_exon_variant	Exon 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NDP	ENST00000642620.1 link	c.385G>T	p.Glu129*	stop_gained	Exon 3 of 3		NM_000266.4	ENSP00000495972.1	Q00604
NDP	ENST00000647044.1 link	c.385G>T	p.Glu129*	stop_gained	Exon 4 of 4			ENSP00000495811.1	Q00604
NDP-AS1	ENST00000435093.1 link	n.85C>A		non_coding_transcript_exon_variant	Exon 1 of 5	3
NDP	ENST00000470584.1 link	n.429G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.40e-7

AC:

AN:

1064336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

347012

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25527

American (AMR)

AF:

0.00

AC:

AN:

29480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18736

East Asian (EAS)

AF:

0.00

AC:

AN:

28112

South Asian (SAS)

AF:

0.00

AC:

AN:

50410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38405

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

824723

Other (OTH)

AF:

0.00

AC:

AN:

44844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.97

PhyloP100

7.5

Vest4

0.85

GERP RS

6.0

Mutation Taster

=41/159

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over