rs12480307

Variant names:

• chr20-25078910-T-C
• rs12480307
• NM_014588.6:c.546A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014588.6(VSX1):​c.546A>G​(p.Ala182Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,613,882 control chromosomes in the GnomAD database, including 51,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7407 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44435 hom.)
• Consequence: VSX1 NM_014588.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.59

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 20-25078910-T-C is Benign according to our data. Variant chr20-25078910-T-C is described in ClinVar as [Benign]. Clinvar id is 100940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-25078910-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX1	NM_014588.6	c.546A>G	p.Ala182Ala	synonymous_variant	Exon 3 of 5	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9	c.546A>G	p.Ala182Ala	synonymous_variant	Exon 3 of 5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44251 AN: 151910 Hom.: 7383 Cov.: 32

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.224

Gnomad OTH AF: 0.285

GnomAD3 exomes AF: 0.259 AC: 65077 AN: 251480 Hom.: 10142 AF XY: 0.252 AC XY: 34218 AN XY: 135914

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.428

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.288

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.249

GnomAD4 exome AF: 0.237 AC: 346964 AN: 1461854 Hom.: 44435 Cov.: 39 AF XY: 0.237 AC XY: 172500 AN XY: 727232

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.412

Gnomad4 ASJ exome AF: 0.315

Gnomad4 EAS exome AF: 0.00892

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.192

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.292 AC: 44324 AN: 152028 Hom.: 7407 Cov.: 32 AF XY: 0.288 AC XY: 21422 AN XY: 74326

Gnomad4 AFR AF: 0.440

Gnomad4 AMR AF: 0.339

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.203

Gnomad4 NFE AF: 0.224

Gnomad4 OTH AF: 0.280

Alfa AF: 0.263 Hom.: 3691

Bravo AF: 0.308

Asia WGS AF: 0.161 AC: 563 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.23
DANN	Benign	0.51

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

Other links and lift over

dbSNP: rs12480307; hg19: chr20-25059546; COSMIC: COSV65021892; COSMIC: COSV65021892;