chrX-43958645-T-C

Position:

• chrX-43958645-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 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:3
• Conservation: PhyloP100: 5.42

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

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• 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 id is 10687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDP	NM_000266.4	c.1A>G	p.Met1?	start_lost	2/3	ENST00000642620.1	NP_000257.1
NDP-AS1	NR_046631.1	n.467-2140T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDP	ENST00000642620.1	c.1A>G	p.Met1?	start_lost	2/3		NM_000266.4	ENSP00000495972	P1
NDP-AS1	ENST00000435093.1	n.467-2140T>C		intron_variant, non_coding_transcript_variant		3
NDP	ENST00000647044.1	c.1A>G	p.Met1?	start_lost	3/4			ENSP00000495811	P1
NDP	ENST00000470584.1	n.218+73A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrophia bulborum hereditaria Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

This sequence change affects the initiator methionine of the NDP mRNA. The next in-frame methionine is located at codon 12. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with Norrie disease (PMID: 7627181, 7814011, 14635119, 26547627). ClinVar contains an entry for this variant (Variation ID: 10687). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
PROVEAN	Benign	-0.55	.;N;.
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		0.14	B;B;B
Vest4		0.82
MutPred		0.99		Loss of catalytic residue at M1 (P = 0.0199);Loss of catalytic residue at M1 (P = 0.0199);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

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

Other links and lift over

dbSNP: rs28933685; hg19: chrX-43817891;