rs7226481

Positions:

• chr18-59269163-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013435.3(RAX):​c.882A>G​(p.Gln294=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,579,814 control chromosomes in the GnomAD database, including 65,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5620 hom., cov: 33)
  • Exomes 𝑓: 0.29 (60218 hom.)
• Consequence: RAX NM_013435.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0410

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 18-59269163-T-C is Benign according to our data. Variant chr18-59269163-T-C is described in ClinVar as [Benign]. Clinvar id is 260310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.041 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAX	NM_013435.3	c.882A>G	p.Gln294=	synonymous_variant	3/3	ENST00000334889.4	NP_038463.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAX	ENST00000334889.4	c.882A>G	p.Gln294=	synonymous_variant	3/3	1	NM_013435.3	ENSP00000334813	P1
RAX	ENST00000256852.7	c.*313A>G		3_prime_UTR_variant	2/2	1		ENSP00000256852

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40174 AN: 151338 Hom.: 5610 Cov.: 33

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.263

GnomAD3 exomes AF: 0.238 AC: 44058 AN: 184906 Hom.: 5584 AF XY: 0.244 AC XY: 24858 AN XY: 101710

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.140

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.127

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.211

Gnomad NFE exome AF: 0.287

Gnomad OTH exome AF: 0.256

GnomAD4 exome AF: 0.287 AC: 409521 AN: 1428360 Hom.: 60218 Cov.: 35 AF XY: 0.285 AC XY: 202045 AN XY: 707904

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.271

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.302

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.265 AC: 40206 AN: 151454 Hom.: 5620 Cov.: 33 AF XY: 0.257 AC XY: 19058 AN XY: 74042

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.259

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.262

Alfa AF: 0.280 Hom.: 1967

Bravo AF: 0.262

Asia WGS AF: 0.238 AC: 827 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Isolated microphthalmia 3 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.59

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: rs7226481; hg19: chr18-56936395; COSMIC: COSV56873883; COSMIC: COSV56873883;