rs2271733

chr18-59273075-G-T

Variant summary

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

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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.892

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
RAX	NM_013435.3	c.132C>A	p.Asp44Glu	missense_variant	1/3	ENST00000334889.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAX	ENST00000334889.4	c.132C>A	p.Asp44Glu	missense_variant	1/3	1	NM_013435.3	P1
RAX	ENST00000256852.7	c.132C>A	p.Asp44Glu	missense_variant	1/2	1
RAX	ENST00000555288.1	c.132C>A	p.Asp44Glu	missense_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35733 AN: 152054 Hom.: 4594 Cov.: 33

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

GnomAD3 exomes AF: 0.224 AC: 29462 AN: 131492 Hom.: 3639 AF XY: 0.230 AC XY: 16383 AN XY: 71260

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 SAS exome AF: 0.233

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.: 36 AF XY: 0.280 AC XY: 191322 AN XY: 682316

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.235 AC: 35732 AN: 152166 Hom.: 4596 Cov.: 33 AF XY: 0.228 AC XY: 16964 AN XY: 74388

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.195

Gnomad4 ASJ AF: 0.269

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.244

Alfa AF: 0.282 Hom.: 9030

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	11
Dann	Benign	0.96
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.55	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.99	P;P
PrimateAI	Pathogenic	0.89	D
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	T
GERP RS		0.12
Varity_R		0.035
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs2271733; hg19: chr18-56940307; COSMIC: COSV56873894; COSMIC: COSV56873894;