19-3769836-C-T

Variant names:

• chr19-3769836-C-T
• rs917546
• NM_001319074.4:c.*785G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001319074.4(RAX2):​c.*785G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 152,594 control chromosomes in the GnomAD database, including 3,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3338 hom., cov: 32)
  • Exomes 𝑓: 0.14 (8 hom.)
• Consequence: RAX2 NM_001319074.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.577
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-3769836-C-T is Benign according to our data. Variant chr19-3769836-C-T is described in ClinVar as Benign. ClinVar VariationId is 328953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 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.*785G>A		3_prime_UTR	Exon 3 of 3	NP_001306003.2	Q96IS3
	RAX2	NM_032753.4		c.*785G>A		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.*785G>A		3_prime_UTR	Exon 3 of 3	ENSP00000450456.3	Q96IS3
	RAX2	ENST00000555978.5	TSL:1	c.*785G>A		3_prime_UTR	Exon 3 of 3	ENSP00000450687.2	Q96IS3

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30452 AN: 151956 Hom.: 3336 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.135 AC: 70 AN: 518 Hom.: 8 Cov.: 0 AF XY: 0.151 AC XY: 56 AN XY: 372

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AC: 0 AN: 0

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

East Asian (EAS) AF: 0.0714 AC: 1 AN: 14

South Asian (SAS) AF: 0.0556 AC: 1 AN: 18

European-Finnish (FIN) AF: 0.250 AC: 4 AN: 16

Middle Eastern (MID) AF: 0.750 AC: 3 AN: 4

European-Non Finnish (NFE) AF: 0.140 AC: 60 AN: 430

Other (OTH) AF: 0.0556 AC: 1 AN: 18

GnomAD4 genome AF: 0.200 AC: 30469 AN: 152076 Hom.: 3338 Cov.: 32 AF XY: 0.198 AC XY: 14731 AN XY: 74352

African (AFR) AF: 0.272 AC: 11270 AN: 41438

American (AMR) AF: 0.161 AC: 2454 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 601 AN: 3472

East Asian (EAS) AF: 0.0257 AC: 133 AN: 5174

South Asian (SAS) AF: 0.155 AC: 747 AN: 4818

European-Finnish (FIN) AF: 0.174 AC: 1845 AN: 10602

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12725 AN: 67966

Other (OTH) AF: 0.211 AC: 445 AN: 2114

Alfa AF: 0.193 Hom.: 1842

Bravo AF: 0.205

Asia WGS AF: 0.105 AC: 367 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Age related macular degeneration 6 (1)
-	-	1	Cone-rod dystrophy 11 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.55
PhyloP100		-0.58
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: rs917546; hg19: chr19-3769834;