ENST00000376707.4:c.711T>A

Variant names:

• chr20-25078745-A-T
• rs56157240
• ENST00000376707.4:c.711T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The ENST00000376707.4(VSX1):​c.711T>A​(p.Pro237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,613,902 control chromosomes in the GnomAD database, including 51,885 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.29 (7409 hom., cov: 31)
  • Exomes 𝑓: 0.24 (44476 hom.)
• Consequence: VSX1 ENST00000376707.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.354
• Publications: 24 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: 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)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP7: Synonymous conserved (PhyloP=-0.354 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.627+84T>A		intron_variant	Intron 3 of 4	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9	c.627+84T>A		intron_variant	Intron 3 of 4	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44275 AN: 151916 Hom.: 7384 Cov.: 31

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.286

GnomAD2 exomes AF: 0.259 AC: 65098 AN: 251466 AF XY: 0.252

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.429

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: 347089 AN: 1461868 Hom.: 44476 Cov.: 43 AF XY: 0.237 AC XY: 172565 AN XY: 727230

African (AFR) AF: 0.452 AC: 15141 AN: 33480

American (AMR) AF: 0.412 AC: 18445 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 8223 AN: 26136

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

South Asian (SAS) AF: 0.289 AC: 24938 AN: 86258

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

Middle Eastern (MID) AF: 0.258 AC: 1490 AN: 5768

European-Non Finnish (NFE) AF: 0.228 AC: 253629 AN: 1111994

Other (OTH) AF: 0.242 AC: 14620 AN: 60394

GnomAD4 genome AF: 0.292 AC: 44349 AN: 152034 Hom.: 7409 Cov.: 31 AF XY: 0.288 AC XY: 21438 AN XY: 74330

African (AFR) AF: 0.439 AC: 18203 AN: 41438

American (AMR) AF: 0.340 AC: 5189 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1124 AN: 3472

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5176

South Asian (SAS) AF: 0.300 AC: 1442 AN: 4806

European-Finnish (FIN) AF: 0.203 AC: 2145 AN: 10584

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15270 AN: 67966

Other (OTH) AF: 0.282 AC: 595 AN: 2112

Alfa AF: 0.254 Hom.: 1786

Bravo AF: 0.308

Asia WGS AF: 0.163 AC: 568 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.53
PhyloP100		-0.35
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: rs56157240; hg19: chr20-25059381; COSMIC: COSV65021405; COSMIC: COSV65021405;