NM_014588.6:c.391C>A

Variant names:

• chr20-25081706-G-T
• rs6050307
• NM_014588.6:c.391C>A
• VSX1 p.Arg131Ser

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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
• Publications: 17 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
• craniofacial anomalies and anterior segment dysgenesis syndrome

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• keratoconus 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae)
• posterior polymorphous corneal dystrophy 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	NM_014588.6	MANE Select	c.391C>A	p.Arg131Ser	missense	Exon 1 of 5	NP_055403.2
	VSX1	NM_001256272.2		c.391C>A	p.Arg131Ser	missense	Exon 1 of 5	NP_001243201.1	Q9NZR4-8
	VSX1	NM_199425.3		c.391C>A	p.Arg131Ser	missense	Exon 1 of 3	NP_955457.1	Q9NZR4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX1	ENST00000376709.9	TSL:1 MANE Select	c.391C>A	p.Arg131Ser	missense	Exon 1 of 5	ENSP00000365899.3	Q9NZR4-1
	VSX1	ENST00000429762.7	TSL:1	c.391C>A	p.Arg131Ser	missense	Exon 1 of 5	ENSP00000401690.3	Q9NZR4-8
	VSX1	ENST00000376707.4	TSL:1	c.391C>A	p.Arg131Ser	missense	Exon 1 of 3	ENSP00000365897.3	Q9NZR4-2

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

GnomAD2 exomes AF: 0.00718 AC: 738 AN: 102810 AF XY: 0.00591

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 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

African (AFR) AF: 0.135 AC: 3847 AN: 28520

American (AMR) AF: 0.00800 AC: 257 AN: 32126

Ashkenazi Jewish (ASJ) AF: 0.00264 AC: 62 AN: 23472

East Asian (EAS) AF: 0.00 AC: 0 AN: 33382

South Asian (SAS) AF: 0.000467 AC: 35 AN: 74944

European-Finnish (FIN) AF: 0.0000296 AC: 1 AN: 33728

Middle Eastern (MID) AF: 0.0137 AC: 54 AN: 3940

European-Non Finnish (NFE) AF: 0.000225 AC: 240 AN: 1066634

Other (OTH) AF: 0.0104 AC: 587 AN: 56414

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

African (AFR) AF: 0.121 AC: 5036 AN: 41556

American (AMR) AF: 0.0138 AC: 212 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67968

Other (OTH) AF: 0.0284 AC: 60 AN: 2116

Alfa AF: 0.00575 Hom.: 54

Bravo AF: 0.0409

Asia WGS AF: 0.00752 AC: 27 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Posterior polymorphous corneal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.78
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.32
Sift	Benign	0.45	T
Sift4G	Benign	0.76	T
PromoterAI		-0.016	Neutral
Varity_R		0.086
gMVP		0.27
Mutation Taster		=94/6	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6050307;

hg19: chr20-25062342;