17-40331253-G-C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_000964.4(RARA):c.35G>C(p.Gly12Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,613,218 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 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000048 ( 0 hom. )
Consequence
RARA
NM_000964.4 missense
NM_000964.4 missense
Scores
5
9
Clinical Significance
Conservation
PhyloP100: 4.27
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=0.22673056).
BS2
?
High AC in GnomAd at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARA | NM_000964.4 | c.35G>C | p.Gly12Ala | missense_variant | 2/9 | ENST00000254066.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARA | ENST00000254066.10 | c.35G>C | p.Gly12Ala | missense_variant | 2/9 | 1 | NM_000964.4 | P4 | |
RARA | ENST00000425707.7 | c.35G>C | p.Gly12Ala | missense_variant | 2/7 | 1 | |||
RARA | ENST00000394089.6 | c.35G>C | p.Gly12Ala | missense_variant | 2/9 | 2 | P4 | ||
RARA | ENST00000577646.5 | c.35G>C | p.Gly12Ala | missense_variant | 3/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249278Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135026
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GnomAD4 exome AF: 0.0000479 AC: 70AN: 1461044Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 726848
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152174Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74340
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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 | Jan 24, 2023 | The c.35G>C (p.G12A) alteration is located in exon 2 (coding exon 1) of the RARA gene. This alteration results from a G to C substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by an alanine (A). 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
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;.;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;T
Polyphen
0.15
.;B;B;.
Vest4
0.45, 0.51
MVP
MPC
1.0
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