rs62637037

Variant names:

• chrX-41474502-G-A
• rs62637037
• NM_001378477.3:c.1034G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PVS1_Strong PP5 BS1_Supporting BS2

The NM_001378477.3(NYX):​c.1034G>A​(p.Trp345*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,206,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: NYX NM_001378477.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 9.72
• Publications: 2 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: Uncertain_significance. The variant received 0 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 7 pathogenic variants in the truncated region.
• PP5: Variant X-41474502-G-A is Pathogenic according to our data. Variant chrX-41474502-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 11421.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000891 (10/112204) while in subpopulation AMR AF = 0.000938 (10/10657). AF 95% confidence interval is 0.000509. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 10 XL,AD gene.

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.1034G>A	p.Trp345*	stop_gained	Exon 3 of 3	NP_001365406.2	Q9GZU5
	NYX	NM_022567.3		c.1034G>A	p.Trp345*	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.1034G>A	p.Trp345*	stop_gained	Exon 3 of 3	ENSP00000367465.2	Q9GZU5
	NYX	ENST00000342595.3	TSL:1	c.1034G>A	p.Trp345*	stop_gained	Exon 2 of 2	ENSP00000340328.3	Q9GZU5
	NYX	ENST00000938151.1		c.1034G>A	p.Trp345*	stop_gained	Exon 3 of 3	ENSP00000608210.1

Frequencies

GnomAD3 genomes AF: 0.0000891 AC: 10 AN: 112204 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000938

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000115 AC: 2 AN: 173400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000739

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1094675 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 361293

African (AFR) AF: 0.00 AC: 0 AN: 26379

American (AMR) AF: 0.0000854 AC: 3 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 30148

South Asian (SAS) AF: 0.00 AC: 0 AN: 53936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4121

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841688

Other (OTH) AF: 0.00 AC: 0 AN: 45997

GnomAD4 genome AF: 0.0000891 AC: 10 AN: 112204 Hom.: 0 Cov.: 24 AF XY: 0.000145 AC XY: 5 AN XY: 34370

African (AFR) AF: 0.00 AC: 0 AN: 30944

American (AMR) AF: 0.000938 AC: 10 AN: 10657

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 2681

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53128

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital stationary night blindness 1A (1)
1	-	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.7
Vest4		0.88
GERP RS		5.5
Mutation Taster		=2/198	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: rs62637037; hg19: chrX-41333755;