rs121908280

chr19-3770916-C-Achr19-3770916-C-Gchr19-3770916-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001319074.4(RAX2):c.260G>T(p.Arg87Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,405,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RAX2 NM_001319074.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.53

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22382966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAX2	NM_001319074.4	c.260G>T	p.Arg87Leu	missense_variant	3/3	ENST00000555633.3
RAX2	NM_032753.4	c.260G>T	p.Arg87Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAX2	ENST00000555633.3	c.260G>T	p.Arg87Leu	missense_variant	3/3	1	NM_001319074.4	P1
RAX2	ENST00000555978.5	c.260G>T	p.Arg87Leu	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000622 AC: 1 AN: 160832 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 88880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405100 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 695610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.75	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.90	N;N
PrimateAI	Uncertain	0.71	T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.98	D;D
Vest4		0.17
MutPred		0.54		Loss of MoRF binding (P = 0.0266);Loss of MoRF binding (P = 0.0266);
MVP		0.10
MPC		0.33
ClinPred		0.64	D
GERP RS		0.80
Varity_R		0.28
gMVP		0.69

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: rs121908280; hg19: chr19-3770914;