rs149918940

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001319074.4(RAX2):c.432G>A(p.Ala144=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,532,820 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 2 hom. )

Consequence

RAX2
NM_001319074.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.63

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 19-3770744-C-T is Benign according to our data. Variant chr19-3770744-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262101.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2}. Variant chr19-3770744-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.63 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0011 (167/152302) while in subpopulation NFE AF= 0.002 (136/68012). AF 95% confidence interval is 0.00173. There are 0 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAX2	NM_001319074.4 linkuse as main transcript	c.432G>A	p.Ala144=	synonymous_variant	3/3	ENST00000555633.3
RAX2	NM_032753.4 linkuse as main transcript	c.432G>A	p.Ala144=	synonymous_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAX2	ENST00000555633.3 linkuse as main transcript	c.432G>A	p.Ala144=	synonymous_variant	3/3	1	NM_001319074.4	P1
RAX2	ENST00000555978.5 linkuse as main transcript	c.432G>A	p.Ala144=	synonymous_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000719

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00121

AC:

154

AN:

127308

Hom.:

AF XY:

0.00115

AC XY:

AN XY:

69682

show subpopulations

Gnomad AFR exome

AF:

0.000529

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.000126

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000449

Gnomad FIN exome

AF:

0.000530

Gnomad NFE exome

AF:

0.00225

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00157

AC:

2165

AN:

1380518

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1077

AN XY:

681342

show subpopulations

Gnomad4 AFR exome

AF:

0.000323

Gnomad4 AMR exome

AF:

0.00158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000253

Gnomad4 FIN exome

AF:

0.000350

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152302

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000718

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00200

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.000994

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone-rod dystrophy 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Age related macular degeneration 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

Cadd

Benign

3.0

Dann

Benign

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over