X-41447899-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PP3_StrongPP5_ModerateBS2

The NM_001378477.3(NYX):c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,208,675 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

NYX
NM_001378477.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.227

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

BayesDel_addAF computational evidence supports a deleterious effect, 0.602

PP5

Variant X-41447899-C-T is Pathogenic according to our data. Variant chrX-41447899-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1975933.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NYX	NM_001378477.3 link	c.-6C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	ENST00000378220.3	NP_001365406.2
NYX	NM_001378477.3 link	c.-6C>T	5_prime_UTR_variant	Exon 2 of 3	ENST00000378220.3	NP_001365406.2
NYX	NM_022567.3 link	c.-6C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2		NP_072089.2	Q9GZU5
NYX	NM_022567.3 link	c.-6C>T	5_prime_UTR_variant	Exon 1 of 2		NP_072089.2	Q9GZU5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NYX	ENST00000378220 link	c.-6C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 3	1	NM_001378477.3	ENSP00000367465.2	Q9GZU5
NYX	ENST00000342595 link	c.-6C>T	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1		ENSP00000340328.3	Q9GZU5
NYX	ENST00000378220 link	c.-6C>T	5_prime_UTR_variant	Exon 2 of 3	1	NM_001378477.3	ENSP00000367465.2	Q9GZU5
NYX	ENST00000342595 link	c.-6C>T	5_prime_UTR_variant	Exon 1 of 2	1		ENSP00000340328.3	Q9GZU5

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33261

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180854

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65816

show subpopulations

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 SAS exome

AF:

0.0000534

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000638

AC:

AN:

1097638

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

363010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000475

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111037

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33261

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Sep 29, 2023

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.Arg4*) in the NYX gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 478 amino acid(s) of the NYX protein. This variant is present in population databases (rs371622974, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with NYX-related conditions. ClinVar contains an entry for this variant (Variation ID: 1975933). This variant disrupts a region of the NYX protein in which other variant(s) (p.Trp350*) have been determined to be pathogenic (PMID: 11062471). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

0.010

CADD

Benign

2.0

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.012

Vest4

0.45

GERP RS

-0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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