rs62637037

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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. Fraction of 0.277 CDS is truncated, and there are 2 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 id is 11421.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1}.

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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 5 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.:

AF XY:

0.000145

AC XY:

AN XY:

34370

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

GnomAD3 exomes

AF:

0.0000115

AC:

AN:

173400

Hom.:

AF XY:

0.00

AC XY:

AN XY:

61388

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000854

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000891

AC:

AN:

112204

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

34370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000938

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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

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. -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

DANN

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

Vest4

0.88

GERP RS

5.5

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over