20-25075765-T-C

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.*496A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 156,814 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.034 (114 hom., cov: 33)
  • Exomes 𝑓: 0.038 (10 hom.)
• Consequence: VSX1 NM_014588.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.30

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=-0.91).
• BP6: Variant 20-25075765-T-C is Benign according to our data. Variant chr20-25075765-T-C is described in ClinVar as [Benign]. Clinvar id is 337948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0342 (5201/152172) while in subpopulation NFE AF= 0.051 (3471/68022). AF 95% confidence interval is 0.0496. There are 114 homozygotes in gnomad4. There are 2442 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 5204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX1	NM_014588.6	c.*496A>G		3_prime_UTR_variant	5/5	ENST00000376709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX1	ENST00000376709.9	c.*496A>G		3_prime_UTR_variant	5/5	1	NM_014588.6	P1

Frequencies

GnomAD3 genomes AF: 0.0342 AC: 5204 AN: 152054 Hom.: 115 Cov.: 33

Gnomad AFR AF: 0.00956

Gnomad AMI AF: 0.0463

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0511

Gnomad OTH AF: 0.0501

GnomAD4 exome AF: 0.0383 AC: 178 AN: 4642 Hom.: 10 Cov.: 0 AF XY: 0.0339 AC XY: 80 AN XY: 2362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0208

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0150

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0442

Gnomad4 OTH exome AF: 0.0385

GnomAD4 genome AF: 0.0342 AC: 5201 AN: 152172 Hom.: 114 Cov.: 33 AF XY: 0.0328 AC XY: 2442 AN XY: 74394

Gnomad4 AFR AF: 0.00953

Gnomad4 AMR AF: 0.0468

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0510

Gnomad4 OTH AF: 0.0496

Alfa AF: 0.0416 Hom.: 38

Bravo AF: 0.0353

Asia WGS AF: 0.0100 AC: 35 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 13, 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	-0.91
Cadd	Benign	0.025
Dann	Benign	0.60

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: rs76499395; hg19: chr20-25056401;