18-59273075-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_013435.3(RAX):c.132C>A(p.Asp44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,534,892 control chromosomes in the GnomAD database, including 61,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4596 hom., cov: 33)

Exomes 𝑓: 0.28 ( 56574 hom. )

Consequence

RAX
NM_013435.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.892

Publications

21 publications found

Variant links:

Genes affected

RAX (HGNC:18662): (retina and anterior neural fold homeobox) This gene encodes a homeobox-containing transcription factor that functions in eye development. The gene is expressed early in the eye primordia, and is required for retinal cell fate determination and also regulates stem cell proliferation. Mutations in this gene have been reported in patients with defects in ocular development, including microphthalmia, anophthalmia, and coloboma.[provided by RefSeq, Oct 2009]

RAX Gene-Disease associations (from GenCC):

isolated microphthalmia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
isolated anophthalmia-microphthalmia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
coloboma
Inheritance: AR Classification: LIMITED Submitted by: G2P

RAX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028769076).

BP6

Variant 18-59273075-G-T is Benign according to our data. Variant chr18-59273075-G-T is described in ClinVar as Benign. ClinVar VariationId is 260309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX	NM_013435.3 link	c.132C>A	p.Asp44Glu	missense_variant	Exon 1 of 3	ENST00000334889.4	NP_038463.2	Q9Y2V3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAX	ENST00000334889.4 link	c.132C>A	p.Asp44Glu	missense_variant	Exon 1 of 3	1	NM_013435.3	ENSP00000334813.3	Q9Y2V3-1
RAX	ENST00000256852.7 link	c.132C>A	p.Asp44Glu	missense_variant	Exon 1 of 2	1		ENSP00000256852.7	Q9Y2V3-2
RAX	ENST00000555288.1 link	c.132C>A	p.Asp44Glu	missense_variant	Exon 2 of 2	3		ENSP00000450583.1	G3V2C8
RAX	ENST00000591550.1 link	n.-155C>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

35733

AN:

152054

Hom.:

4594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.168

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.269

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.200

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.244

GnomAD2 exomes

AF:

0.224

AC:

29462

AN:

131492

AF XY:

0.230

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.272

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.210

Gnomad NFE exome

AF:

0.287

Gnomad OTH exome

AF:

0.248

GnomAD4 exome

AF:

0.282

AC:

389830

AN:

1382726

Hom.:

56574

Cov.:

AF XY:

0.280

AC XY:

191322

AN XY:

682316

show subpopulations

African (AFR)

AF:

0.161

AC:

5086

AN:

31530

American (AMR)

AF:

0.144

AC:

5130

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

6844

AN:

25140

East Asian (EAS)

AF:

0.206

AC:

7358

AN:

35692

South Asian (SAS)

AF:

0.231

AC:

18310

AN:

79190

European-Finnish (FIN)

AF:

0.211

AC:

7078

AN:

33606

Middle Eastern (MID)

AF:

0.244

AC:

1389

AN:

5684

European-Non Finnish (NFE)

AF:

0.300

AC:

323402

AN:

1078354

Other (OTH)

AF:

0.263

AC:

15233

AN:

57846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

19198

38397

57595

76794

95992

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10812

21624

32436

43248

54060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.235

AC:

35732

AN:

152166

Hom.:

4596

Cov.:

AF XY:

0.228

AC XY:

16964

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.168

AC:

6968

AN:

41572

American (AMR)

AF:

0.195

AC:

2989

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.269

AC:

934

AN:

3466

East Asian (EAS)

AF:

0.140

AC:

716

AN:

5128

South Asian (SAS)

AF:

0.232

AC:

1118

AN:

4828

European-Finnish (FIN)

AF:

0.200

AC:

2122

AN:

10596

Middle Eastern (MID)

AF:

0.233

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.293

AC:

19937

AN:

67972

Other (OTH)

AF:

0.244

AC:

514

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1445

2890

4336

5781

7226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

370

740

1110

1480

1850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.277

Hom.:

12603

Bravo

AF:

0.228

TwinsUK

AF:

0.297

AC:

1102

ALSPAC

AF:

0.313

AC:

1205

ESP6500AA

AF:

0.157

AC:

490

ESP6500EA

AF:

0.266

AC:

1484

ExAC

AF:

0.199

AC:

4013

Asia WGS

AF:

0.226

AC:

786

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Isolated microphthalmia 3

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

.;T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.55

T;T;T

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.

PhyloP100

-0.89

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.64

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0040

.;B;.

Vest4

0.036

MutPred

0.095

Gain of methylation at K43 (P = 0.0894);Gain of methylation at K43 (P = 0.0894);Gain of methylation at K43 (P = 0.0894);

MPC

0.75

ClinPred

0.0097

GERP RS

0.12

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.035

gMVP

0.34

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over