Genetic Variant VSX1:p.Ser6Ser (chr20-25082079-C-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014588.6(VSX1):c.18G>T(p.Ser6Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 1,538,440 control chromosomes in the GnomAD database, including 6,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 434 hom., cov: 33)

Exomes 𝑓: 0.086 ( 5779 hom. )

Consequence

VSX1
NM_014588.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0370

Publications

13 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 20-25082079-C-A is Benign according to our data. Variant chr20-25082079-C-A is described in ClinVar as Benign. ClinVar VariationId is 260423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.037 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0968 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014588.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VSX1	NM_014588.6	MANE Select	c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 5	NP_055403.2
VSX1	NM_001256272.2		c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 5	NP_001243201.1
VSX1	NM_199425.3		c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 3	NP_955457.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
VSX1	ENST00000376709.9	TSL:1 MANE Select	c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 5	ENSP00000365899.3
VSX1	ENST00000429762.7	TSL:1	c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 5	ENSP00000401690.3
VSX1	ENST00000376707.4	TSL:1	c.18G>T	p.Ser6Ser	synonymous	Exon 1 of 3	ENSP00000365897.3

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9655

AN:

152184

Hom.:

434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0543

Gnomad ASJ

AF:

0.0841

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0863

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0988

Gnomad OTH

AF:

0.0544

GnomAD2 exomes

AF:

0.0576

AC:

7685

AN:

133482

AF XY:

0.0559

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.0385

Gnomad ASJ exome

AF:

0.0823

Gnomad EAS exome

AF:

0.0000902

Gnomad FIN exome

AF:

0.0946

Gnomad NFE exome

AF:

0.0953

Gnomad OTH exome

AF:

0.0593

GnomAD4 exome

AF:

0.0857

AC:

118833

AN:

1386140

Hom.:

5779

Cov.:

AF XY:

0.0836

AC XY:

57231

AN XY:

684290

show subpopulations

African (AFR)

AF:

0.0129

AC:

411

AN:

31984

American (AMR)

AF:

0.0408

AC:

1463

AN:

35884

Ashkenazi Jewish (ASJ)

AF:

0.0788

AC:

1983

AN:

25166

East Asian (EAS)

AF:

0.000138

AC:

AN:

36334

South Asian (SAS)

AF:

0.0178

AC:

1413

AN:

79484

European-Finnish (FIN)

AF:

0.0968

AC:

3254

AN:

33622

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

0.0980

AC:

105842

AN:

1080290

Other (OTH)

AF:

0.0755

AC:

4378

AN:

57990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

7666

15332

22998

30664

38330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3816

7632

11448

15264

19080

<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:

0.0634

AC:

9651

AN:

152300

Hom.:

434

Cov.:

AF XY:

0.0618

AC XY:

4603

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0160

AC:

666

AN:

41588

American (AMR)

AF:

0.0542

AC:

829

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0841

AC:

292

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0174

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0863

AC:

916

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0988

AC:

6716

AN:

67980

Other (OTH)

AF:

0.0539

AC:

114

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

467

935

1402

1870

2337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0791

Hom.:

266

Bravo

AF:

0.0584

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Posterior polymorphous corneal dystrophy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.6

(source)

DANN

Benign

0.82

PhyloP100

-0.037

PromoterAI

0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over