chrX-41473490-GC-TT

Position:

• chrX-41473490-GC-TT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001378477.3(NYX):​c.23-1_23delGCinsTT​(p.Ala8Val) variant causes a splice acceptor, missense, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NYX NM_001378477.3 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.68

Genes affected

NYX (HGNC:8082): (nyctalopin) The product of this gene belongs to the small leucine-rich proteoglycan (SLRP) family of proteins. Defects in this gene are the cause of congenital stationary night blindness type 1 (CSNB1), also called X-linked congenital stationary night blindness (XLCSNB). CSNB1 is a rare inherited retinal disorder characterized by impaired scotopic vision, myopia, hyperopia, nystagmus and reduced visual acuity. The role of other SLRP proteins suggests that mutations in this gene disrupt developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB. [provided by RefSeq, Oct 2008]

NYX (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of 22, new splice context is: gtggtcctcggcctgcccAGcgc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41473490-GC-TT is Pathogenic according to our data. Variant chrX-41473490-GC-TT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496942.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
NYX	NM_001378477.3	c.23-1_23delGCinsTT	p.Ala8Val	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3	c.23-1_23delGCinsTT	p.Ala8Val	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant			NP_072089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NYX	ENST00000378220.3	c.23-1_23delGCinsTT	p.Ala8Val	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		1	NM_001378477.3	ENSP00000367465.2
NYX	ENST00000342595.3	c.23-1_23delGCinsTT	p.Ala8Val	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		1		ENSP00000340328.3
NYX	ENST00000486842.1	n.276-1_276delGCinsTT		splice_acceptor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2014	- -

Congenital stationary night blindness 1A Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 08, 2022

- -

NYX-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The NYX c.38-1_38delinsTT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in the hemizygous state in individuals with congenital stationary night blindness (Kim et al. 2021. PubMed ID: 34064005; Moon et al. 2021. PubMed ID: 35052368). This variant has not been reported in a large population database, indicating this variant is rare. Variants that disrupt the consensus splice site are expected to be pathogenic. Given all the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555967031; hg19: chrX-41332743;