chr17-40354318-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_000964.4(RARA):c.824C>T(p.Thr275Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
RARA
NM_000964.4 missense
NM_000964.4 missense
Scores
7
8
3
Clinical Significance
Conservation
PhyloP100: 7.90
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 -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, RARA
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.82
BS2
?
High AC in GnomAdExome at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARA | NM_000964.4 | c.824C>T | p.Thr275Met | missense_variant | 7/9 | ENST00000254066.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARA | ENST00000254066.10 | c.824C>T | p.Thr275Met | missense_variant | 7/9 | 1 | NM_000964.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250942Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135710
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461848Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727222
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
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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 | Feb 22, 2023 | The c.824C>T (p.T275M) alteration is located in exon 7 (coding exon 6) of the RARA gene. This alteration results from a C to T substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Benign
DEOGEN2
Uncertain
D;D;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.
Sift4G
Benign
T;T;D;T;T;T
Polyphen
D;D;.;.;.;.
Vest4
MutPred
Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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