chrX-41474502-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PVS1_StrongPP5BS1_SupportingBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 9.72

Publications

2 publications found

Variant links:

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

NYX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NYX	NM_001378477.3 link	c.1034G>A	p.Trp345*	stop_gained	Exon 3 of 3	ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3 link	c.1034G>A	p.Trp345*	stop_gained	Exon 2 of 2		NP_072089.2	Q9GZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NYX	ENST00000378220.3 link	c.1034G>A	p.Trp345*	stop_gained	Exon 3 of 3	1	NM_001378477.3	ENSP00000367465.2		Q9GZU5
NYX	ENST00000342595.3 link	c.1034G>A	p.Trp345*	stop_gained	Exon 2 of 2	1		ENSP00000340328.3		Q9GZU5

Frequencies

GnomAD3 genomes

AF:

0.0000891

AC:

AN:

112204

Hom.:

Cov.:

show subpopulations

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:

AN:

173400

AF XY:

0.00

show subpopulations

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:

AN:

1094675

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361293

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.0000854

AC:

AN:

35127

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19335

East Asian (EAS)

AF:

0.00

AC:

AN:

30148

South Asian (SAS)

AF:

0.00

AC:

AN:

53936

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4121

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841688

Other (OTH)

AF:

0.00

AC:

AN:

45997

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000891

AC:

AN:

112204

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34370

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30944

American (AMR)

AF:

0.000938

AC:

AN:

10657

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53128

Other (OTH)

AF:

0.00

AC:

AN:

1514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000289

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp350*) in the NYX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 132 amino acid(s) of the NYX protein. This variant is present in population databases (rs62637037, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with congenital stationary night blindness (PMID: 11062471). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11421). For these reasons, this variant has been classified as Pathogenic. -

Congenital stationary night blindness 1A

Pathogenic:1

Nov 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

PhyloP100

9.7

Vest4

0.88

GERP RS

5.5

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over