20-25081706-G-T

Position:

• chr20-25081706-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014588.6(VSX1):​c.391C>A​(p.Arg131Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00694 in 1,505,368 control chromosomes in the GnomAD database, including 562 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (291 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (271 hom.)
• Consequence: VSX1 NM_014588.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.778

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016133189).
• BP6: Variant 20-25081706-G-T is Benign according to our data. Variant chr20-25081706-G-T is described in ClinVar as [Benign]. Clinvar id is 337965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSX1	NM_014588.6	c.391C>A	p.Arg131Ser	missense_variant	1/5	ENST00000376709.9	NP_055403.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSX1	ENST00000376709.9	c.391C>A	p.Arg131Ser	missense_variant	1/5	1	NM_014588.6	ENSP00000365899.3

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5329 AN: 152094 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.00718 AC: 738 AN: 102810 Hom.: 35 AF XY: 0.00591 AC XY: 337 AN XY: 56976

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.00715

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000738

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000763

Gnomad OTH exome AF: 0.00743

GnomAD4 exome AF: 0.00376 AC: 5083 AN: 1353160 Hom.: 271 Cov.: 31 AF XY: 0.00340 AC XY: 2266 AN XY: 666934

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000467

Gnomad4 FIN exome AF: 0.0000296

Gnomad4 NFE exome AF: 0.000225

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0352 AC: 5358 AN: 152208 Hom.: 291 Cov.: 33 AF XY: 0.0338 AC XY: 2514 AN XY: 74448

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0284

Alfa AF: 0.00232 Hom.: 12

Bravo AF: 0.0409

ESP6500AA AF: 0.0922 AC: 328

ESP6500EA AF: 0.00192 AC: 13

ExAC AF: 0.00544 AC: 332

Asia WGS AF: 0.00752 AC: 27 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2019	This variant is associated with the following publications: (PMID: 30090183, 15051220) -

Posterior polymorphous corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	4.6
DANN	Benign	0.85
DEOGEN2	Benign	0.057	.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.56	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.64	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.057
MVP		0.40
MPC		0.12
ClinPred		0.0017	T
GERP RS		-3.9
Varity_R		0.086
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6050307; hg19: chr20-25062342;