NM_014588.6:c.391C>G

Variant names:

• chr20-25081706-G-C
• rs6050307
• NM_014588.6:c.391C>G
• VSX1 p.Arg131Gly

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.391C>G​(p.Arg131Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,353,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R131S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: VSX1 NM_014588.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.778
• 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
• 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: 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=0.079139024).

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>G	p.Arg131Gly	missense	Exon 1 of 5	NP_055403.2
	VSX1	NM_001256272.2		c.391C>G	p.Arg131Gly	missense	Exon 1 of 5	NP_001243201.1	Q9NZR4-8
	VSX1	NM_199425.3		c.391C>G	p.Arg131Gly	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>G	p.Arg131Gly	missense	Exon 1 of 5	ENSP00000365899.3	Q9NZR4-1
	VSX1	ENST00000429762.7	TSL:1	c.391C>G	p.Arg131Gly	missense	Exon 1 of 5	ENSP00000401690.3	Q9NZR4-8
	VSX1	ENST00000376707.4	TSL:1	c.391C>G	p.Arg131Gly	missense	Exon 1 of 3	ENSP00000365897.3	Q9NZR4-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1353172 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 666942

African (AFR) AF: 0.00 AC: 0 AN: 28530

American (AMR) AF: 0.00 AC: 0 AN: 32128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 74944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3940

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066634

Other (OTH) AF: 0.00 AC: 0 AN: 56414

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.2
DANN	Benign	0.89
DEOGEN2	Benign	0.075	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.78
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.28
Sift	Benign	0.061	T
Sift4G	Benign	0.38	T
PromoterAI		-0.016	Neutral
Varity_R		0.067
gMVP		0.27
Mutation Taster		=96/4	polymorphism

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

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;