17-40356110-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_000964.4(RARA):c.1273G>A(p.Gly425Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 657,024 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 (★).
Frequency
Genomes: 𝑓 0.000036 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000014 ( 0 hom. )
Consequence
RARA
NM_000964.4 missense
NM_000964.4 missense
Scores
9
9
Clinical Significance
Conservation
PhyloP100: 2.13
Genes affected
RARA (HGNC:9864): (retinoic acid receptor alpha) This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RARA
BP4
?
Computational evidence support a benign effect (MetaRNN=0.19676292).
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARA | NM_000964.4 | c.1273G>A | p.Gly425Arg | missense_variant | 9/9 | ENST00000254066.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARA | ENST00000254066.10 | c.1273G>A | p.Gly425Arg | missense_variant | 9/9 | 1 | NM_000964.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000358 AC: 5AN: 139706Hom.: 0 Cov.: 30
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GnomAD4 exome AF: 0.0000135 AC: 7AN: 517318Hom.: 0 Cov.: 25 AF XY: 0.0000181 AC XY: 5AN XY: 275844
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GnomAD4 genome ? AF: 0.0000358 AC: 5AN: 139706Hom.: 0 Cov.: 30 AF XY: 0.0000295 AC XY: 2AN XY: 67732
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2023 | The c.1273G>A (p.G425R) alteration is located in exon 9 (coding exon 8) of the RARA gene. This alteration results from a G to A substitution at nucleotide position 1273, causing the glycine (G) at amino acid position 425 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.;.;.
MutationTaster
Benign
D;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
P;P;.;.;.
Vest4
MutPred
Gain of solvent accessibility (P = 0.0674);Gain of solvent accessibility (P = 0.0674);.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at