Genetic Variant VSX1:p.Leu17Gln (chr20-25082047-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014588.6(VSX1):c.50T>A(p.Leu17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L17V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

VSX1
NM_014588.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0960

Publications

0 publications found

Variant links:

Genes affected

VSX1 (HGNC:12723): (visual system homeobox 1) The protein encoded by this gene contains a paired-like homeodomain and binds to the core of the locus control region of the red/green visual pigment gene cluster. The encoded protein may regulate expression of the cone opsin genes early in development. Mutations in this gene can cause posterior polymorphous corneal dystrophy and keratoconus. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

VSX1 Gene-Disease associations (from GenCC):

posterior polymorphous corneal dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
keratoconus 1
Inheritance: AD, Unknown Classification: LIMITED Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
craniofacial anomalies and anterior segment dysgenesis syndrome
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
posterior polymorphous corneal dystrophy 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

VSX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22602269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6 link	c.50T>A	p.Leu17Gln	missense_variant	Exon 1 of 5	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9 link	c.50T>A	p.Leu17Gln	missense_variant	Exon 1 of 5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1385978

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32000

American (AMR)

AF:

0.00

AC:

AN:

35942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25160

East Asian (EAS)

AF:

0.00

AC:

AN:

36352

South Asian (SAS)

AF:

0.00

AC:

AN:

79482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5126

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1080380

Other (OTH)

AF:

0.00

AC:

AN:

57934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

.;.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.65

T;T;T;T

M_CAP

Pathogenic

0.78

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

-0.076

MutationAssessor

Benign

1.8

L;L;L;L

PhyloP100

-0.096

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.22

T;T;T;T

Sift4G

Benign

0.41

T;T;T;T

Polyphen

0.12

B;B;B;B

Vest4

0.17

MutPred

0.38

Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);Loss of stability (P = 0.0139);

MVP

0.83

MPC

0.54

ClinPred

0.28

GERP RS

0.73

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.20

gMVP

0.50

Mutation Taster

=54/46

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over