rs281865194

Positions:

chrX-41473528-GGCCTGCGCCCGCGCTTGTCCCGCC-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP3

The NM_001378477.3(NYX):c.70_93delCGCGCTTGTCCCGCCGCCTGCGCC(p.Arg24_Ala31del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 110,973 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000056 ( 0 hom. 4 hem. )

Failed GnomAD Quality Control

Consequence

NYX
NM_001378477.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 9.69

Variant links:

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 links:

NYX (HGNC:):

NYX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant X-41473528-GGCCTGCGCCCGCGCTTGTCCCGCC-G is Pathogenic according to our data. Variant chrX-41473528-GGCCTGCGCCCGCGCTTGTCCCGCC-G is described in ClinVar as [Pathogenic]. Clinvar id is 99841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-41473528-GGCCTGCGCCCGCGCTTGTCCCGCC-G is described in Lovd as [Likely_pathogenic].

BP3

Nonframeshift variant in repetitive region in NM_001378477.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NYX	NM_001378477.3 linkuse as main transcript	c.70_93delCGCGCTTGTCCCGCCGCCTGCGCC	p.Arg24_Ala31del	conservative_inframe_deletion	3/3	ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3 linkuse as main transcript	c.70_93delCGCGCTTGTCCCGCCGCCTGCGCC	p.Arg24_Ala31del	conservative_inframe_deletion	2/2		NP_072089.2	Q9GZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NYX	ENST00000378220.3 linkuse as main transcript	c.70_93delCGCGCTTGTCCCGCCGCCTGCGCC	p.Arg24_Ala31del	conservative_inframe_deletion	3/3	1	NM_001378477.3	ENSP00000367465.2	Q9GZU5
NYX	ENST00000342595.3 linkuse as main transcript	c.70_93delCGCGCTTGTCCCGCCGCCTGCGCC	p.Arg24_Ala31del	conservative_inframe_deletion	2/2	1		ENSP00000340328.3	Q9GZU5
NYX	ENST00000486842.1 linkuse as main transcript	n.323_346delCGCGCTTGTCCCGCCGCCTGCGCC		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

110973

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33499

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:

0.0000381

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000564

AC:

AN:

886556

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

267588

show subpopulations

Gnomad4 AFR exome

AF:

0.0000558

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000543

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000180

AC:

AN:

110973

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

33499

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:

0.0000381

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This variant, c.85_108del, results in the deletion of 8 amino acid(s) of the NYX protein (p.Arg29_Ala36del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs281865194, gnomAD 0.01%). This variant has been observed in individuals with congenital stationary night blindness (PMID: 11062471, 19578023). It has also been observed to segregate with disease in related individuals. This variant is also known as 85‚Äì108del24nt (RACPAACA29-36del). ClinVar contains an entry for this variant (Variation ID: 99841). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2023	In-frame deletion of 8 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18617546, 11062471, 19578023) -

Congenital stationary night blindness 1A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	May 08, 2024	The NYX c.85_108del (p.Arg29_Ala36del) variant has been reported in 29 individuals in eight families with X-linked complete congenital stationary night blindness (Bech-Hansen NT et al., PMID: 11062471; Zeitz C et al., PMID: 19578023). A genotype analysis of the X chromosomes with this deletion suggest that this is a common founder mutation. This variant is only observed on 1/19,558 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant is predicted to cause a change in the length of the protein due to an in-frame deletion of eight amino acids in a non-repeat region. This variant has been reported in the ClinVar database as a germline pathogenic variant by six submitters. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2000	- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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