chrX-41473558-C-A

Variant names:

• chrX-41473558-C-A
• rs62637021
• NM_001378477.3:c.90C>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001378477.3(NYX):​c.90C>A​(p.Cys30*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 899,690 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C30C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000022 (0 hom. 0 hem.)
• Consequence: NYX NM_001378477.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.694
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• congenital stationary night blindness 1A

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• NYX-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 52 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-41473558-C-A is Pathogenic according to our data. Variant chrX-41473558-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11422.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378477.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NYX	NM_001378477.3	MANE Select	c.90C>A	p.Cys30*	stop_gained	Exon 3 of 3	NP_001365406.2	Q9GZU5
	NYX	NM_022567.3		c.90C>A	p.Cys30*	stop_gained	Exon 2 of 2	NP_072089.2	Q9GZU5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NYX	ENST00000378220.3	TSL:1 MANE Select	c.90C>A	p.Cys30*	stop_gained	Exon 3 of 3	ENSP00000367465.2	Q9GZU5
	NYX	ENST00000342595.3	TSL:1	c.90C>A	p.Cys30*	stop_gained	Exon 2 of 2	ENSP00000340328.3	Q9GZU5
	NYX	ENST00000938151.1		c.90C>A	p.Cys30*	stop_gained	Exon 3 of 3	ENSP00000608210.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000222 AC: 2 AN: 899690 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 273356

African (AFR) AF: 0.00 AC: 0 AN: 18006

American (AMR) AF: 0.00 AC: 0 AN: 9397

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12342

East Asian (EAS) AF: 0.00 AC: 0 AN: 18721

South Asian (SAS) AF: 0.00 AC: 0 AN: 33752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2800

European-Non Finnish (NFE) AF: 0.00000134 AC: 1 AN: 745162

Other (OTH) AF: 0.0000272 AC: 1 AN: 36774

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital stationary night blindness 1A (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		0.69
Vest4		0.66
GERP RS		2.8
Mutation Taster		=12/188	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs62637021; hg19: chrX-41332811;