20-25076061-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014588.6(VSX1):c.*200G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 692,238 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 33)
  • Exomes 𝑓: 0.014 (72 hom.)
• Consequence: VSX1 NM_014588.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 20-25076061-C-A is Benign according to our data. Variant chr20-25076061-C-A is described in ClinVar as [Benign]. Clinvar id is 337951.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-25076061-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0122 (1864/152312) while in subpopulation AMR AF= 0.0206 (316/15310). AF 95% confidence interval is 0.0188. There are 18 homozygotes in gnomad4. There are 957 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1865 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX1	NM_014588.6	c.*200G>T		3_prime_UTR_variant	5/5	ENST00000376709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX1	ENST00000376709.9	c.*200G>T		3_prime_UTR_variant	5/5	1	NM_014588.6	P1

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1865 AN: 152194 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0211

GnomAD4 exome AF: 0.0138 AC: 7464 AN: 539926 Hom.: 72 Cov.: 7 AF XY: 0.0133 AC XY: 3745 AN XY: 280568

Gnomad4 AFR exome AF: 0.00252

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.00732

Gnomad4 EAS exome AF: 0.0000640

Gnomad4 SAS exome AF: 0.00959

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0122 AC: 1864 AN: 152312 Hom.: 18 Cov.: 33 AF XY: 0.0128 AC XY: 957 AN XY: 74476

Gnomad4 AFR AF: 0.00267

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.0156

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.00859 Hom.: 2

Bravo AF: 0.0120

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polymorphous corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.76
Cadd	Benign	0.36
Dann	Benign	0.78

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: rs75590263; hg19: chr20-25056697;