rs12480307

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 37 publications found

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: Laboratory for Molecular Medicine, G2P, 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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 100940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	NM_014588.6	MANE Select	c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 5	NP_055403.2
	VSX1	NM_001256272.2		c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 5	NP_001243201.1	Q9NZR4-8
	VSX1	NM_199425.3		c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 3	NP_955457.1	Q9NZR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	ENST00000376709.9	TSL:1 MANE Select	c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 5	ENSP00000365899.3	Q9NZR4-1
	VSX1	ENST00000429762.7	TSL:1	c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 5	ENSP00000401690.3	Q9NZR4-8
	VSX1	ENST00000376707.4	TSL:1	c.546A>G	p.Ala182Ala	synonymous	Exon 3 of 3	ENSP00000365897.3	Q9NZR4-2

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

GnomAD2 exomes AF: 0.259 AC: 65077 AN: 251480 AF XY: 0.252

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 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

African (AFR) AF: 0.451 AC: 15114 AN: 33480

American (AMR) AF: 0.412 AC: 18432 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8222 AN: 26136

East Asian (EAS) AF: 0.00892 AC: 354 AN: 39700

South Asian (SAS) AF: 0.289 AC: 24930 AN: 86256

European-Finnish (FIN) AF: 0.192 AC: 10249 AN: 53418

Middle Eastern (MID) AF: 0.255 AC: 1468 AN: 5754

European-Non Finnish (NFE) AF: 0.228 AC: 253588 AN: 1111992

Other (OTH) AF: 0.242 AC: 14607 AN: 60394

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

African (AFR) AF: 0.440 AC: 18214 AN: 41424

American (AMR) AF: 0.339 AC: 5175 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1123 AN: 3468

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5174

South Asian (SAS) AF: 0.299 AC: 1439 AN: 4810

European-Finnish (FIN) AF: 0.203 AC: 2150 AN: 10600

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.224 AC: 15254 AN: 67960

Other (OTH) AF: 0.280 AC: 592 AN: 2112

Alfa AF: 0.262 Hom.: 4931

Bravo AF: 0.308

Asia WGS AF: 0.161 AC: 563 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.236

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Posterior polymorphous corneal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.23
DANN	Benign	0.51
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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