chr20-25082047-A-T

Variant names:

• chr20-25082047-A-T
• rs74315436
• NM_014588.6:c.50T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014588.6(VSX1):​c.50T>A​(p.Leu17Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L17V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: VSX1 NM_014588.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22602269).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014588.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	NM_014588.6	MANE Select	c.50T>A	p.Leu17Gln	missense	Exon 1 of 5	NP_055403.2
	VSX1	NM_001256272.2		c.50T>A	p.Leu17Gln	missense	Exon 1 of 5	NP_001243201.1
	VSX1	NM_199425.3		c.50T>A	p.Leu17Gln	missense	Exon 1 of 3	NP_955457.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	ENST00000376709.9	TSL:1 MANE Select	c.50T>A	p.Leu17Gln	missense	Exon 1 of 5	ENSP00000365899.3
	VSX1	ENST00000429762.7	TSL:1	c.50T>A	p.Leu17Gln	missense	Exon 1 of 5	ENSP00000401690.3
	VSX1	ENST00000376707.4	TSL:1	c.50T>A	p.Leu17Gln	missense	Exon 1 of 3	ENSP00000365897.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385978 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 684176

African (AFR) AF: 0.00 AC: 0 AN: 32000

American (AMR) AF: 0.00 AC: 0 AN: 35942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 36352

South Asian (SAS) AF: 0.00 AC: 0 AN: 79482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5126

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080380

Other (OTH) AF: 0.00 AC: 0 AN: 57934

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.096
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.15
Sift	Benign	0.22	T
Sift4G	Benign	0.41	T
Polyphen		0.12	B
Vest4		0.17
MutPred		0.38		Loss of stability (P = 0.0139)
MVP		0.83
MPC		0.54
ClinPred		0.28	T
GERP RS		0.73
PromoterAI		-0.11	Neutral
Varity_R		0.20
gMVP		0.50
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs74315436; hg19: chr20-25062683;