rs7226481

Variant names:

• chr18-59269163-T-C
• rs7226481
• NM_013435.3:c.882A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013435.3(RAX):​c.882A>G​(p.Gln294Gln) 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
• Publications: 14 publications found

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: Labcorp Genetics (formerly Invitae), G2P
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• coloboma

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013435.3. 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
	RAX	NM_013435.3	MANE Select	c.882A>G	p.Gln294Gln	synonymous	Exon 3 of 3	NP_038463.2	Q9Y2V3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAX	ENST00000334889.4	TSL:1 MANE Select	c.882A>G	p.Gln294Gln	synonymous	Exon 3 of 3	ENSP00000334813.3	Q9Y2V3-1
	RAX	ENST00000256852.7	TSL:1	c.*313A>G		3_prime_UTR	Exon 2 of 2	ENSP00000256852.7	Q9Y2V3-2

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

GnomAD2 exomes AF: 0.238 AC: 44058 AN: 184906 AF XY: 0.244

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 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

African (AFR) AF: 0.262 AC: 8586 AN: 32738

American (AMR) AF: 0.146 AC: 5824 AN: 39940

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 6924 AN: 25506

East Asian (EAS) AF: 0.202 AC: 7731 AN: 38278

South Asian (SAS) AF: 0.257 AC: 21435 AN: 83294

European-Finnish (FIN) AF: 0.209 AC: 10052 AN: 48082

Middle Eastern (MID) AF: 0.252 AC: 1321 AN: 5252

European-Non Finnish (NFE) AF: 0.302 AC: 331525 AN: 1096234

Other (OTH) AF: 0.273 AC: 16123 AN: 59036

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

African (AFR) AF: 0.264 AC: 10908 AN: 41330

American (AMR) AF: 0.207 AC: 3160 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 935 AN: 3456

East Asian (EAS) AF: 0.142 AC: 728 AN: 5122

South Asian (SAS) AF: 0.259 AC: 1245 AN: 4806

European-Finnish (FIN) AF: 0.202 AC: 2115 AN: 10480

Middle Eastern (MID) AF: 0.243 AC: 70 AN: 288

European-Non Finnish (NFE) AF: 0.297 AC: 20127 AN: 67714

Other (OTH) AF: 0.262 AC: 550 AN: 2100

Alfa AF: 0.280 Hom.: 1967

Bravo AF: 0.262

Asia WGS AF: 0.238 AC: 827 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Isolated microphthalmia 3 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		0.041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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