rs1555967263

chrX-41474389-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001378477.3(NYX):c.921C>G(p.Asn307Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). 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)
• Consequence: NYX NM_001378477.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.11

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 99844.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-41474389-C-G is Pathogenic according to our data. Variant chrX-41474389-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438056.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-41474389-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NYX	NM_001378477.3	c.921C>G	p.Asn307Lys	missense_variant	3/3	ENST00000378220.3
NYX	NM_022567.3	c.921C>G	p.Asn307Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NYX	ENST00000378220.3	c.921C>G	p.Asn307Lys	missense_variant	3/3	1	NM_001378477.3	P1
NYX	ENST00000342595.3	c.921C>G	p.Asn307Lys	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Abnormality of the eye Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

Rare ocular disorder associated to additional undetermined phenotypes -

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
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555967263; hg19: chrX-41333642;