19-3770967-G-A

Position:

• chr19-3770967-G-A

Variant summary

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

The ENST00000555633.3(RAX2):​c.217-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,550,918 control chromosomes in the GnomAD database, including 23,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1885 hom., cov: 33)
  • Exomes 𝑓: 0.17 (21551 hom.)
• Consequence: RAX2 ENST00000555633.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005479
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.18

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=-0.83).
• BP6: Variant 19-3770967-G-A is Benign according to our data. Variant chr19-3770967-G-A is described in ClinVar as [Benign]. Clinvar id is 96230.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.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_116142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001319074.4	ENSP00000450456	P1
RAX2	ENST00000555978.5	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000450687	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23000 AN: 152068 Hom.: 1884 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0251

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.158 AC: 24393 AN: 154002 Hom.: 2151 AF XY: 0.163 AC XY: 13841 AN XY: 85028

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.0206

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.172 AC: 240457 AN: 1398732 Hom.: 21551 Cov.: 30 AF XY: 0.172 AC XY: 118949 AN XY: 692290

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.0281

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.161

Gnomad4 NFE exome AF: 0.182

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.151 AC: 23018 AN: 152186 Hom.: 1885 Cov.: 33 AF XY: 0.150 AC XY: 11186 AN XY: 74402

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.0251

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.163

Alfa AF: 0.169 Hom.: 411

Bravo AF: 0.150

Asia WGS AF: 0.0940 AC: 328 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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. -

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	-0.83
CADD	Benign	6.0
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.0060
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: rs79588413; hg19: chr19-3770965;