X-43949816-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP3BP6BS1BS2

The NM_000266.4(NDP):c.385G>A(p.Glu129Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00004 in 1,176,447 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E129E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000029 ( 0 hom. 10 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.54

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000266.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

BP6

Variant X-43949816-C-T is Benign according to our data. Variant chrX-43949816-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377374.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000143 (16/112111) while in subpopulation AMR AF= 0.000942 (10/10619). AF 95% confidence interval is 0.00051. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4 linkuse as main transcript	c.385G>A	p.Glu129Lys	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1 linkuse as main transcript	n.85C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NDP	ENST00000642620.1 linkuse as main transcript	c.385G>A	p.Glu129Lys	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1 linkuse as main transcript	n.85C>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1 linkuse as main transcript	c.385G>A	p.Glu129Lys	missense_variant	4/4			P1
NDP	ENST00000470584.1 linkuse as main transcript	n.429G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

112111

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34269

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000942

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000933

AC:

AN:

128650

Hom.:

AF XY:

0.0000719

AC XY:

AN XY:

41706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000477

Gnomad ASJ exome

AF:

0.000154

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1064336

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

347012

show subpopulations

Gnomad4 AFR exome

AF:

0.000118

Gnomad4 AMR exome

AF:

0.000509

Gnomad4 ASJ exome

AF:

0.0000534

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.0000446

GnomAD4 genome

AF:

0.000143

AC:

AN:

112111

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34269

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000942

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.00000872

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2023	This missense change has been observed in individual(s) with Peters anomaly (PMID: 25182519). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 129 of the NDP protein (p.Glu129Lys). This variant is present in population databases (rs756474198, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 377374). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NDP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25182519) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Pathogenic

0.20

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;D;D

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.76

D;D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Benign

0.90

L;L;L

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.82

Polyphen

1.0

D;D;D

Vest4

0.85

MutPred

0.32

Gain of methylation at E129 (P = 6e-04);Gain of methylation at E129 (P = 6e-04);Gain of methylation at E129 (P = 6e-04);

MVP

0.90

MPC

1.5

ClinPred

0.29

GERP RS

6.0

Varity_R

0.72

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over