NM_001319074.4:c.*1082_*1092delTCCCAGATCAC

Variant names:

• chr19-3769528-GGTGATCTGGGA-G
• rs143816706
• NM_001319074.4:c.*1082_*1092delTCCCAGATCAC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001319074.4(RAX2):​c.*1082_*1092delTCCCAGATCAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 152,692 control chromosomes in the GnomAD database, including 278 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.038 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (0 hom.)
• Consequence: RAX2 NM_001319074.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.472
• Publications: 0 publications found

Genes affected

RAX2 (HGNC:18286): (retina and anterior neural fold homeobox 2) This gene encodes a homeodomain-containing protein that plays a role in eye development. Mutation of this gene causes age-related macular degeneration type 6, an eye disorder resulting in accumulations of protein and lipid beneath the retinal pigment epithelium and within the Bruch's membrane. Defects in this gene can also cause cone-rod dystrophy type 11, a disease characterized by the initial degeneration of cone photoreceptor cells and resulting in loss of color vision and visual acuity, followed by the degeneration of rod photoreceptor cells, which progresses to night blindness and the loss of peripheral vision. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

RAX2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa

  Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Franklin by Genoox
• cone-rod dystrophy 11

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa 95

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 19-3769528-GGTGATCTGGGA-G is Benign according to our data. Variant chr19-3769528-GGTGATCTGGGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 328947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319074.4. 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
	RAX2	NM_001319074.4	MANE Select	c.*1082_*1092delTCCCAGATCAC		3_prime_UTR	Exon 3 of 3	NP_001306003.2	Q96IS3
	RAX2	NM_032753.4		c.*1082_*1092delTCCCAGATCAC		3_prime_UTR	Exon 3 of 3	NP_116142.1	Q96IS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAX2	ENST00000555633.3	TSL:1 MANE Select	c.*1082_*1092delTCCCAGATCAC		3_prime_UTR	Exon 3 of 3	ENSP00000450456.3	Q96IS3
	RAX2	ENST00000555978.5	TSL:1	c.*1082_*1092delTCCCAGATCAC		3_prime_UTR	Exon 3 of 3	ENSP00000450687.2	Q96IS3

Frequencies

GnomAD3 genomes AF: 0.0381 AC: 5794 AN: 152140 Hom.: 277 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.0359

GnomAD4 exome AF: 0.00461 AC: 2 AN: 434 Hom.: 0 AF XY: 0.00667 AC XY: 2 AN XY: 300

African (AFR) AF: 0.00 AC: 0 AN: 12

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.00 AC: 0 AN: 42

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00654 AC: 2 AN: 306

Other (OTH) AF: 0.00 AC: 0 AN: 30

GnomAD4 genome AF: 0.0381 AC: 5795 AN: 152258 Hom.: 278 Cov.: 32 AF XY: 0.0375 AC XY: 2790 AN XY: 74450

African (AFR) AF: 0.114 AC: 4725 AN: 41534

American (AMR) AF: 0.0167 AC: 255 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0185 AC: 196 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00726 AC: 494 AN: 68018

Other (OTH) AF: 0.0355 AC: 75 AN: 2110

Alfa AF: 0.0275 Hom.: 12

Bravo AF: 0.0418

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cone-Rod Dystrophy, Dominant (1)
-	-	1	Macular degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143816706; hg19: chr19-3769526;