X-43949932-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5

The NM_000266.4(NDP):c.269G>A(p.Arg90His) variant causes a missense change. The variant allele was found at a frequency of 0.0000655 in 1,205,187 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000069 ( 0 hom. 19 hem. )

Consequence

NDP
NM_000266.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.70

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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, 6 uncertain in NM_000266.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-43949933-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373948.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDP	NM_000266.4 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	3/3	ENST00000642620.1
NDP-AS1	NR_046631.1 linkuse as main transcript	n.201C>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.269G>A	p.Arg90His	missense_variant	3/3		NM_000266.4	P1
NDP-AS1	ENST00000435093.1 linkuse as main transcript	n.201C>T		non_coding_transcript_exon_variant	1/5	3
NDP	ENST00000647044.1 linkuse as main transcript	c.269G>A	p.Arg90His	missense_variant	4/4			P1
NDP	ENST00000470584.1 linkuse as main transcript	n.313G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111565

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33755

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000236

AC:

AN:

169831

Hom.:

AF XY:

0.00

AC XY:

AN XY:

56509

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000695

AC:

AN:

1093622

Hom.:

Cov.:

AF XY:

0.0000528

AC XY:

AN XY:

359720

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000333

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000857

Gnomad4 OTH exome

AF:

0.0000653

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111565

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33755

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 22, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 90 of the NDP protein (p.Arg90His). 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. This variant disrupts the p.Arg90 amino acid residue in NDP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14635119). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 812352). This missense change has been observed in individual(s) with Norrie disease (PMID: 31456290). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Laboratoire Génétique Moléculaire, CHRU TOURS	Jun 04, 2019	- -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Moderate, PM5_Moderate, PP3_Supporting -

Atrophia bulborum hereditaria

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2024

Variant summary: NDP c.269G>A (p.Arg90His) results in a non-conservative amino acid change located in the Cystine knot, C-terminal (IPR006207) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.6e-05 in 1205187 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NDP causing Atrophia bulborum hereditaria (6.6e-05 vs ND), allowing no conclusion about variant significance. c.269G>A has been reported in the literature in individuals affected with Atrophia bulborum hereditaria. These report(s) do not provide unequivocal conclusions about association of the variant with Atrophia bulborum hereditaria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 812352). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.13

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;D;D

FATHMM_MKL

Uncertain

0.83

M_CAP

Pathogenic

0.71

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

0.55

N;N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

Polyphen

1.0

D;D;D

Vest4

0.17

MVP

0.93

MPC

1.6

ClinPred

0.38

GERP RS

6.0

Varity_R

0.56

gMVP

0.87

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