19-3769472-G-A

Position:

• chr19-3769472-G-A

Variant summary

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

The NM_001319074.4(RAX2):​c.*1149C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,444 control chromosomes in the GnomAD database, including 2,036 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2035 hom., cov: 33)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: RAX2 NM_001319074.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.49

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-3769472-G-A is Benign according to our data. Variant chr19-3769472-G-A is described in ClinVar as [Benign]. Clinvar id is 328945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAX2	NM_001319074.4	c.*1149C>T		3_prime_UTR_variant	3/3	ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4	c.*1149C>T		3_prime_UTR_variant	3/3		NP_116142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633	c.*1149C>T		3_prime_UTR_variant	3/3	1	NM_001319074.4	ENSP00000450456.3
RAX2	ENST00000555978	c.*1149C>T		3_prime_UTR_variant	3/3	1		ENSP00000450687.2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 24036 AN: 152056 Hom.: 2030 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.142

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.111 AC: 30 AN: 270 Hom.: 1 Cov.: 0 AF XY: 0.114 AC XY: 21 AN XY: 184

Gnomad4 AFR exome AF: 0.750

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0625

GnomAD4 genome AF: 0.158 AC: 24061 AN: 152174 Hom.: 2035 Cov.: 33 AF XY: 0.156 AC XY: 11596 AN XY: 74400

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.142

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.176

Alfa AF: 0.170 Hom.: 711

Bravo AF: 0.159

Asia WGS AF: 0.0970 AC: 339 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cone-rod dystrophy 11 Benign:1

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 provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Age related macular degeneration 6 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.47
DANN	Benign	0.96

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: rs1860322; hg19: chr19-3769470;