19-3770916-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_001319074.4(RAX2):c.260G>A(p.Arg87Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,557,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

RAX2
NM_001319074.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 3.53

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32189253).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00019 (29/152304) while in subpopulation SAS AF= 0.000415 (2/4824). AF 95% confidence interval is 0.00023. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAX2	NM_001319074.4 linkuse as main transcript	c.260G>A	p.Arg87Gln	missense_variant	3/3	ENST00000555633.3
RAX2	NM_032753.4 linkuse as main transcript	c.260G>A	p.Arg87Gln	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAX2	ENST00000555633.3 linkuse as main transcript	c.260G>A	p.Arg87Gln	missense_variant	3/3	1	NM_001319074.4	P1
RAX2	ENST00000555978.5 linkuse as main transcript	c.260G>A	p.Arg87Gln	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000118

AC:

AN:

160832

Hom.:

AF XY:

0.000146

AC XY:

AN XY:

88880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000404

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000223

Gnomad OTH exome

AF:

0.000431

GnomAD4 exome

AF:

0.000221

AC:

310

AN:

1405102

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

151

AN XY:

695610

show subpopulations

Gnomad4 AFR exome

AF:

0.0000613

Gnomad4 AMR exome

AF:

0.0000264

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000265

Gnomad4 SAS exome

AF:

0.0000492

Gnomad4 FIN exome

AF:

0.0000288

Gnomad4 NFE exome

AF:

0.000269

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.000190

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000281

AC:

ExAC

AF:

0.0000711

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Age related macular degeneration 6

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 20, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 87 of the RAX2 protein (p.Arg87Gln). This variant is present in population databases (rs121908280, gnomAD 0.02%). This missense change has been observed in individual(s) with age-related macular degeneration (PMID: 15028672). ClinVar contains an entry for this variant (Variation ID: 1240). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RAX2 function (PMID: 15028672). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.12

Cadd

Benign

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

0.097

Eigen_PC

Benign

-0.00063

FATHMM_MKL

Benign

0.12

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

0.90

L;L

MutationTaster

Benign

0.0038

A;A

PrimateAI

Uncertain

0.67

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.98

D;D

Vest4

0.27

MVP

0.54

MPC

0.30

ClinPred

0.16

GERP RS

0.80

Varity_R

0.15

gMVP

0.57

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