X-41474389-C-A

Variant names:

• chrX-41474389-C-A
• rs1555967263
• NM_001378477.3:c.921C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PS1 PM5 PP3_Strong BS2

The NM_001378477.3(NYX):​c.921C>A​(p.Asn307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,093,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N307S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000027 (0 hom. 3 hem.)
• Consequence: NYX NM_001378477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_001378477.3 (NYX) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-41474388-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 99844.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• BS2: High Hemizygotes in GnomAdExome4 at 3 AD,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NYX	NM_001378477.3	c.921C>A	p.Asn307Lys	missense_variant	Exon 3 of 3	ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3	c.921C>A	p.Asn307Lys	missense_variant	Exon 2 of 2		NP_072089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NYX	ENST00000378220.3	c.921C>A	p.Asn307Lys	missense_variant	Exon 3 of 3	1	NM_001378477.3	ENSP00000367465.2
NYX	ENST00000342595.3	c.921C>A	p.Asn307Lys	missense_variant	Exon 2 of 2	1		ENSP00000340328.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1093865 Hom.: 0 Cov.: 32 AF XY: 0.00000830 AC XY: 3 AN XY: 361429

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19366

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 842003

Other (OTH) AF: 0.00 AC: 0 AN: 46058

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.5	H;H
PhyloP100		2.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.88		Gain of ubiquitination at N312 (P = 0.0267);Gain of ubiquitination at N312 (P = 0.0267);
MVP		0.88
MPC		2.0
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.73
gMVP		1.0
Mutation Taster		=22/78	disease causing

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: rs1555967263; hg19: chrX-41333642;