Genetic Variant NM_001378477.3:c.266G>C (chrX-41473734-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001378477.3(NYX):c.266G>C(p.Arg89Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NYX
NM_001378477.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 2.75

Publications

3 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: G2P, Labcorp Genetics (formerly Invitae)
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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.869

PP5

Variant X-41473734-G-C is Pathogenic according to our data. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NYX	NM_001378477.3	MANE Select	c.266G>C	p.Arg89Pro	missense	Exon 3 of 3	NP_001365406.2	Q9GZU5
	NYX	NM_022567.3		c.266G>C	p.Arg89Pro	missense	Exon 2 of 2	NP_072089.2	Q9GZU5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NYX	ENST00000378220.3	TSL:1 MANE Select	c.266G>C	p.Arg89Pro	missense	Exon 3 of 3	ENSP00000367465.2	Q9GZU5
NYX	ENST00000342595.3	TSL:1	c.266G>C	p.Arg89Pro	missense	Exon 2 of 2	ENSP00000340328.3	Q9GZU5
NYX	ENST00000938151.1		c.266G>C	p.Arg89Pro	missense	Exon 3 of 3	ENSP00000608210.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1045231

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

338291

African (AFR)

AF:

0.00

AC:

AN:

23093

American (AMR)

AF:

0.00

AC:

AN:

31067

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17902

East Asian (EAS)

AF:

0.00

AC:

AN:

26148

South Asian (SAS)

AF:

0.00

AC:

AN:

50199

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3992

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

821645

Other (OTH)

AF:

0.00

AC:

AN:

43827

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital stationary night blindness 1A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.7

PhyloP100

2.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.0

REVEL

Benign

0.28

Sift

Benign

0.12

Sift4G

Benign

0.19

Polyphen

0.98

Vest4

0.47

MutPred

0.83

Loss of MoRF binding (P = 0.025)

MVP

0.99

MPC

2.1

ClinPred

0.81

GERP RS

4.1

Varity_R

0.76

gMVP

0.83

Mutation Taster

=26/74

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over