14-74239513-T-TG

Position:

• chr14-74239513-T-TG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_182894.3(VSX2):​c.-43dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,528,572 control chromosomes in the GnomAD database, including 40 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (38 hom.)
• Consequence: VSX2 NM_182894.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.33

Genes affected

VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00313 (434/138766) while in subpopulation SAS AF= 0.0121 (52/4302). AF 95% confidence interval is 0.00947. There are 2 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX2	NM_182894.3	c.-43dup		5_prime_UTR_variant	1/5	ENST00000261980.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX2	ENST00000261980.3	c.-43dup		5_prime_UTR_variant	1/5	1	NM_182894.3	P1

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 435 AN: 138696 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000708

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00490

Gnomad ASJ AF: 0.0157

Gnomad EAS AF: 0.000411

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.0400

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00972

GnomAD3 exomes AF: 0.00482 AC: 710 AN: 147414 Hom.: 10 AF XY: 0.00532 AC XY: 423 AN XY: 79446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00380

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0000945

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.000470

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00966

GnomAD4 exome AF: 0.00314 AC: 4365 AN: 1389806 Hom.: 38 Cov.: 32 AF XY: 0.00351 AC XY: 2401 AN XY: 684964

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00435

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.0000281

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00492

GnomAD4 genome AF: 0.00313 AC: 434 AN: 138766 Hom.: 2 Cov.: 33 AF XY: 0.00305 AC XY: 205 AN XY: 67248

Gnomad4 AFR AF: 0.000706

Gnomad4 AMR AF: 0.00489

Gnomad4 ASJ AF: 0.0157

Gnomad4 EAS AF: 0.000413

Gnomad4 SAS AF: 0.0121

Gnomad4 FIN AF: 0.000110

Gnomad4 NFE AF: 0.00323

Gnomad4 OTH AF: 0.00912

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

VSX2-related Microphthalmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs557085907; hg19: chr14-74706216;