chrX-41473526-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_001378477.3(NYX):c.58G>A(p.Gly20Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000462 in 995,422 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000044 ( 0 hom. 12 hem. )

Consequence

NYX
NM_001378477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.50

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2772264).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000631 (7/111006) while in subpopulation NFE AF = 0.000133 (7/52551). AF 95% confidence interval is 0.0000622. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 23. 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 7 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NYX	NM_001378477.3 link	c.58G>A	p.Gly20Arg	missense_variant	Exon 3 of 3	ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3 link	c.58G>A	p.Gly20Arg	missense_variant	Exon 2 of 2		NP_072089.2	Q9GZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NYX	ENST00000378220.3 link	c.58G>A	p.Gly20Arg	missense_variant	Exon 3 of 3	1	NM_001378477.3	ENSP00000367465.2	Q9GZU5
NYX	ENST00000342595.3 link	c.58G>A	p.Gly20Arg	missense_variant	Exon 2 of 2	1		ENSP00000340328.3	Q9GZU5
NYX	ENST00000486842.1 link	n.311G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000631

AC:

AN:

111006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

12761

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000441

AC:

AN:

884416

Hom.:

Cov.:

AF XY:

0.0000448

AC XY:

AN XY:

267602

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17890

American (AMR)

AF:

0.00

AC:

AN:

8565

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11775

East Asian (EAS)

AF:

0.00

AC:

AN:

18924

South Asian (SAS)

AF:

0.00

AC:

AN:

30839

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21906

Middle Eastern (MID)

AF:

0.000436

AC:

AN:

2292

European-Non Finnish (NFE)

AF:

0.0000503

AC:

AN:

736193

Other (OTH)

AF:

0.0000278

AC:

AN:

36032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000631

AC:

AN:

111006

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30811

American (AMR)

AF:

0.00

AC:

AN:

10607

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3503

South Asian (SAS)

AF:

0.00

AC:

AN:

2764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5734

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

52551

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.73G>A (p.G25R) alteration is located in exon 2 (coding exon 2) of the NYX gene. This alteration results from a G to A substitution at nucleotide position 73, causing the glycine (G) at amino acid position 25 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NYX protein function. ClinVar contains an entry for this variant (Variation ID: 1025763). This variant has not been reported in the literature in individuals affected with NYX-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 25 of the NYX protein (p.Gly25Arg). -

Congenital stationary night blindness 1A

Uncertain:1

Feb 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.18

T;T

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.62

.;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PhyloP100

4.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.11

Sift

Benign

0.081

T;T

Sift4G

Benign

0.097

T;T

Polyphen

0.0

B;B

Vest4

0.093

MutPred

0.70

Gain of MoRF binding (P = 0.0441);Gain of MoRF binding (P = 0.0441);

MVP

0.82

MPC

0.96

ClinPred

0.086

GERP RS

1.4

Varity_R

0.071

gMVP

0.33

Mutation Taster

=92/8

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over