rs104894910

Variant names:

• chrX-41473734-G-A
• rs104894910
• NM_001378477.3:c.266G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-41473734-G-A
• chrX-41473734-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001378477.3(NYX):​c.266G>A​(p.Arg89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000957 in 1,045,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: NYX NM_001378477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75
• 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: Uncertain_significance. The variant received 4 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-41473734-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11424.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NYX	NM_001378477.3	MANE Select	c.266G>A	p.Arg89His	missense	Exon 3 of 3	NP_001365406.2
	NYX	NM_022567.3		c.266G>A	p.Arg89His	missense	Exon 2 of 2	NP_072089.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NYX	ENST00000378220.3	TSL:1 MANE Select	c.266G>A	p.Arg89His	missense	Exon 3 of 3	ENSP00000367465.2
	NYX	ENST00000342595.3	TSL:1	c.266G>A	p.Arg89His	missense	Exon 2 of 2	ENSP00000340328.3
	NYX	ENST00000486842.1	TSL:3	n.*25G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.57e-7 AC: 1 AN: 1045221 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 338281

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23093

American (AMR) AF: 0.00 AC: 0 AN: 31066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17901

East Asian (EAS) AF: 0.00 AC: 0 AN: 26148

South Asian (SAS) AF: 0.00 AC: 0 AN: 50199

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3992

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 821638

Other (OTH) AF: 0.00 AC: 0 AN: 43826

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.090	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.13
MutPred		0.59		Gain of sheet (P = 0.0266)
MVP		0.98
MPC		2.0
ClinPred		0.69	D
GERP RS		4.1
Varity_R		0.14
gMVP		0.53
Mutation Taster		=70/30	polymorphism

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: rs104894910; hg19: chrX-41332987;